Independent and Correlated Role of Apolipoprotein E ɛ 4 Genotype and Herpes Simplex Virus Type 1 in Alzheimer’s Disease

Abstract

The ɛ4 allele of the Apolipoprotein E (APOE) gene in individuals infected by Herpes simplex virus type 1 (HSV-1) has been demonstrated to be a risk factor in Alzheimer’s disease (AD). APOE-ɛ4 reduces the levels of neuronal cholesterol, interferes with the transportation of cholesterol, impairs repair of synapses, decreases the clearance of neurotoxic peptide amyloid-β (Aβ), and promotes the deposition of amyloid plaque, and eventually may cause development of AD. HSV-1 enters host cells and can infect the olfactory system, trigeminal ganglia, entorhinal cortex, and hippocampus, and may cause AD-like pathological changes. The lifecycle of HSV-1 goes through a long latent phase. HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production in AD. It should be noted that interferons display antiviral activity in HSV-1-infected AD patients. Reactivated HSV-1 is associated with infectious burden in cognitive decline and AD. Finally, HSV-1 DNA has been confirmed as present in human brains and is associated with APOE ɛ4 in AD. HSV-1 and APOE ɛ4 increase the risk of AD and relate to abnormal autophagy, higher concentrations of HSV-1 DNA in AD, and formation of Aβ plaques and neurofibrillary tangles.

Keywords

Alzheimer’s disease apolipoprotein E cytokine estrogen therapy herpes simplex virus type 1 infectious burden interferon

INTRODUCTION

Alzheimer’s disease (AD) is devastating and the most common neurodegenerative disorder for the aging population worldwide, doubling the risk every five years for individuals over the age of 65 and affecting up to 50% over the age of 85 [1, 2]. AD is consistent with clinical syndromes, such as cognitive profiles and classical symptoms and now with a specific biological neuropathological presence: extracellular deposition of diffuse neuritic plaques and intraneuronal neurofibrillary tangles (NFTs) resulting from aggregated hyperphosphorylated tau protein (P-tau) [3, 4]. However, an endless parade of mid-to-late-stage clinical trial failures has frustrated pharmaceutical development for AD and no disease modifying therapies are currently available, which are direly needed to prevent or slow the rate of disease progression [4].

Late-onset AD, accounting for approximately 95% of AD cases, appears to have multiple susceptibility genes, especially the ɛ4 of the Apolipoprotein E (APOE ɛ4) gene [5, 6]. Apolipoprotein E (APOE) protein could influence neurite outgrowth, synaptic plasticity and amyloid accrual, cholesterol metabolism, and particularly the risk of AD [7 –10]. Interestingly, the negative effect of APOE ɛ3/ɛ4 on AD progression may increase AD risk about 4-fold in women in contrast with men, as compared to the ɛ3 allele of APOE (APOE3) [11, 12].

Herpes simplex virus type 1 (HSV-1) DNA resides in the brains of elderly people at a high proportion, whereas some individuals infected by HSV-1 do not develop AD [13]. Herpes viruses evade, manipulate, and exploit host immune responses and have been found to leave a footprint of the host immune system resulting from an arms race between viral evasion and host immune defense [13]. HSV-1 specific neutralizing ability of AD sera was reduced because HSV-1 specific immunoglobulin G (IgG) 3 were more frequently detected in mild cognitive impairment (MCI), compared to AD and healthy controls groups, but the presence of IgG3 was at a relatively high quantity [14]. New data from the World Health Organization indicated that almost 3.7 billion people, who were under the age of 50, or 67% of the population, had HSV-1 infection (oral or genital) in 2016, and prevalence of the infection was highest in Africa (88%) and lowest in the Americas (45%) [15]. The inhibition of HSV-1 autophagy in host cells and viral induced amyloid-β protein precursor (AβPP) processing alterations could result in accumulation of intraneuronal amyloid-β (Aβ) [16]. The virus interacts with oxidative stress to significantly enhance the effects of accumulation of Aβ and autophagy impairment induced by HSV-1 [17].

HSV-1 can directly access the central nervous system (CNS) bypassing the brain stem by olfactory bulb (OB), and the levels of latency-associated transcripts isolated from the OB were marginally above uninfected controls during HSV-1 latency [18]. There is a strong need to demonstrate the route of HSV-1 infection in animal models and humans, and to explore the contribution of herpes simplex viruses to AD etiology and pathogenesis. Here we present recent discoveries relevant to methods of HSV-1 entry and regions of HSV-1 infection (Table 1). It is likely that HSV-1 infection is more prevalent in older adults, because HSV-1 DNA presents in brain autopsies of non-AD elderly at a significant frequency [19]. The levels of HSV-1-specific IgG and IgM in blood are not elevated in all studies of AD, which may due to altered immunoglobin levels caused by old and new viral infections and other factors [20, 21]. A viral etiology of AD may be confounded by the result that HSV-1 cannot be the sole cause of AD. Conversely, the bulk of the evidence shows that HSV-1 infection may contribute to AD etiology and pathogenesis.

Table 1

Studies relating entry of HSV-1

Discovery	Method of entry	Region of sample	First author, Year
Herpes simplex virus 1 (HSV-1) DNA was detected from postmortem tissue samples of patients with HSV-1 infection.	Nested polymerase chain reaction (PCR)	Olfactory, Trigeminal ganglion (TG)	Liedtke, 1993 [94]
Latent HSV-1 reactivation occurred decades after the original infection and transported HSV-1 particles.	Latent infection in dorsal root ganglia	TG; Oral area, Locus coeruleus, Hippocampus	Steiner, 2007 [87]
HSV-1 DNA was identified in 90 percent of all patients with clinical AD.	Real-time PCR (RT-PCR)	TG	Hill, 2008 [95]
HSV-1 infection progressed from the nose to the TG and then reemerged in the facial skin.	Live imaging of HSV-1-expressed luciferase	TG, Facial skin	Shivkumar, 2013 [88]
Mac2 from macrophages, CD3 from T lymphocytes, and myeloperoxidase from neutrophils were confirmed in BALB/c mice.	Intra-nasally exerting the HSV-1 17Syn+strain, Immunochemistry	Macrophages, T lymphocytes, Neutrophils	Ball, 2013 [96]
A severe spatial memory ability deficit of mice infected with HSV-1 was detected.	Morris water maze test	BALB/c mice	Ball, 2013 [96]
Flood monocytes infiltrated into the central nervous system (CNS) during experimental herpes simplex virus encephalitis.	Immunohistochemistry analysis, Flow cytometry	CNS in mice, Brainstem, OB, Blood monocyte, Macrophages	Menasria, 2015 [89]
HSV-1 spread from the olfactory epithelium to TG neurons, while SSMs blocked systemic spread.	Myeloid cell infection	Olfactory epithelium, TG	Shivkumar, 2016 [98]
Functional overexpression of vomeronasal organ (VNO) receptors used an HSV-1-derived amplicon.	Ca^2 + imaging, virus-induced overexpression of V1rj2, V2r1b or Fpr3	Native VNO cells	Stein B, 2016 [97]
HSV-1 entered the tree shrew brain following ocular inoculation and detected HSV-1 transcripts during acute infection.	HSV-1 ocular inoculation to tree shrew, In situ hybridization	Most brain regions, OB, Brain stem tissue	Li L, 2016 [99]
HSV-1 infected the OB shortly following ocular infection and exhibited a long-term inflammatory profile.	Inoculated with HSV-1 to scarified corneas of C57BL/6 or reporter-inducible Rosa mice (RosaTd/Tm), RT-PCR, confocal microscopy	OB, T cells	Menendez, 2017 [18]

This review focuses on elucidating the relationship between APOE polymorphism and AD and further demonstrates APOE ɛ4 as an AD-associated risk factor to accelerate pathological characteristics in AD. In addition, the role of herpes simplex virus type 1 in AD is described. In this paper, a cooperative role between the APOE ɛ4 and HSV-1 infection in the etiology of AD is presented.

DIFFERENT STRUCTURAL DOMAINS AND FUNCTIONAL ISOFORMS OF APOLIPOPROTEIN E PROTEIN IN HUMAN

The human APOE gene, located on chromosome 19, is a polymorphic gene with three analogous allelic forms designated ɛ2, ɛ3, and ɛ4, which respectively encode E2, E3, and E4 protein isoforms [22]. APOE protein coded by the APOE gene is a glycoprotein with 299 amino acids, and is a major component of very-low density lipoproteins [23]. Related to human APOE isoforms (E2, E3, and E4), only amino acid positions 158 and/or 112 of these three isoforms of APOE differ (Fig. 1). APOE3 protein contains an arginine at position 158 and a cysteine at 112, whereas APOE4 contains arginine at both positions and APOE2 contains a cysteine at both sites [24, 25]. APOE protein has two main regions: the lipid-binding region at the C-terminal domain and the receptor-binding region at the N-terminal domain, where a flexible hinge joins them [26].

Fig.1

APOE with different protein isoforms, structural domains, and functional regions. APOE protein has 299 amino acids divided to three main domains, including N-terminal domain (purple), hinge domain (blue) and C-terminal domain (green). The hinge domain (blue) is from position 191 to 217. The C-terminal domain (green, 217–299) has a lipid binding region from 247 to 272. The N-terminal domain (purple) involves the receptor binding region (136–150) containing the heparan sulfate proteoglycan (HSPG) binding region (142–147). There different isoforms of APOE protein in the N-terminal domain only have one/two difference of amino acids in 112 and 158 positions, such as APOE2 (two Cys), APOE3 (one Cys and one Arg) and APOE4 (two Arg).

Highly conserved regions representing approximately 47 amino acids (of 299) appear to be related to the primary APOE protein functions by reflecting ligand binding sites and regions involved in the propagation of the arginine-cysteine change at position 112 to distant regions in the N- and C-terminal domains of the protein [27]. Taken together, APOE dimer tandem repeat peptide was found to have activity against HSV-1 and 2 [28]. In addition, an N-terminal fragment of APOE has antiviral activity due to this receptor-binding domain and may cause innate immunity to infection of virus by inhibiting attachment of virus and/or direct disruption of viral particles, subsequently reducing viral entry, suggesting that the peptide participates in preventing viral attachment, interfering with the earliest phase of viral infection [28]. This may structurally explain that APOE protein influences infectivity of HSV-1.

INDEPENDENT FUNCTIONS OF APOE ɛ3, ɛ2, AND ɛ4 GENE POLYMORPHISMS, ESPECIALLY THE AD SUSCEPTIBILITY GENE APOE ɛ4 GENOTYPE

APOE ɛ4 as genetic risk variant in AD

APOE gene in brain is also involved in amyloid accrual, cholesterol metabolism, and AD risk [10]. APOE ɛ4 is linked to a variety of diseases including Lewy body disorders, Parkinson’s disease, stroke, sleep apnea, multiple sclerosis, and AD [29]. APOE3 protein maintains lipid homeostasis and thus shows protection against cardiovascular diseases, while APOE2 protein is connected to dysbetalipoproteinemia [30]. In many studies with APOE ɛ3 as the comparator, APOE ɛ4 has emerged as the greatest genetic risk variant for AD with risk for homozygous carriers increasing over 15-fold, whereas APOE ɛ2 decreases risk 4-fold, regardless of geographical location or race [31]. Intracranial aneurysms with hypertension were associated with the ɛ2 allele and the ɛ2/ɛ3 genotype of APOE in a case-control study [32]. It has been shown previously that the carriage of ɛ4 genotype affects prognosis, pre-symptomatic risk and treatment response for various diseases, such as AD [33]. Indeed, the clearance of soluble Aβ in brain interstitial fluid depended on the expression of APOE protein isoforms [34]. Possession of human APOE ɛ4 caused the greatest accumulation of amyloid in models of AβPP transgenic mouse, compared to APOE ɛ3 and APOE ɛ2 transgenic mice [35]. Nevertheless, the ɛ4 allele of APOE alone is neither sufficient nor necessary for the development of AD [36, 37].

Role of APOE ɛ4 in neuron-associated functions in AD

APOE ɛ4 may be involved in deficiency of neuroprotective functions and toxicity [31, 38]. It is hypothesized that APOE ɛ4 allele is consistent with an increased AD risk-associated hippocampal neurotoxic lifetime exposure and the highest transportation of macromolecules to neurons, such as lipids and proteins [39]. APOE ɛ4 elevated proteolytic degradation reducing the levels of neuronal cholesterol, interferes with the transportation of cholesterol, and impairs function and repair of synapses [40]. Furthermore, future therapies to slow down pruning of synapses might meditate differential effects based on APOE allele subtype [41].

Idiosyncrasies of APOE polymorphisms in women

Interacting differently in women, the genetic risk factor APOE ɛ4 for AD may display an elevated risk of adverse clinical changes from healthy aging to disease [42]. Current findings indicate that the carriage of APOE ɛ4 shows connection with late-life Aβ deposition and midlife dyslipidemia in women primarily [43]. These factors interact resulting in a compounded risk for Aβ deposition twenty years later [43]. Low-density lipoprotein (LDL) cholesterol associated with Aβ notably increases in midlife after adjusting for age, cholesterol medication, cognition, and education, but adjustment for APOE4 protein attenuates LDL cholesterol [43].

The interactive effects of estrogen therapy (ET) and APOE protein on AD pathology are suggested by preclinical studies [44]. ET treatment may be particularly effective at cognition improvement in APOE ɛ4 carriers, even though the published data are inconsistent [45, 46]. In a study with placebo-control, ET was associated with more cognitive decline in APOE ɛ4 positive women than in APOE ɛ4 negative carriers [47, 48]. The Nurses’ Health Study indicated that ET provided no benefits in older women, regardless of APOE genotype. In contrast, hormone replacement therapy (HT) associated with less cognitive decline was significantly pronounced with APOE ɛ4 carriers in follow-up analysis [46, 49]. It has also been demonstrated that HT attenuates the risk of dementia linked with APOE ɛ4, and elevated markers of aging show acceleration in APOE ɛ4 carriers [50].

Possible survival advantages in youth with APOE ɛ4, as an ancestral genotype

The APOE ɛ4 was the first gene in evolution, whereas the ɛ2 and the ɛ3 mutations were respectively produced 80,000 and 300,000 years ago [51]. APOE ɛ3 is the most common allele [52]. However, the driving force for the transformation from ɛ4 to ɛ3 predominance is currently still obscure [41]. APOE ɛ4 may be less prevalent due to the ancestral advantages of the APOE ɛ4 and the evolutionary trade-off of superior performance in youth [41]. Historical lifespans were brief such that advantages in youth associated with the APOE ɛ4 allele might have increased fitness compared to the ɛ3 allele [41].

The ancestral predominance of the ɛ4 allele might have been influenced by protective effects on fertility and reproduction [53, 54]. Furthermore, APOE ɛ4 genotype showed a protective role via a decrease in risk of intracranial aneurysms in a Chinese population [55]. In prehistoric populations with a high carriage of ɛ4 allele, endemic infectious diseases show resistance associated with the predominance of APOE ɛ4 [56, 57]. Studies suggest that carriers of the APOE ɛ4 might display higher mental performance in young healthy subjects [58 –60] with fewer neurons in certain brain regions allocated to memory processes than in non-carriers [61, 62].

EVOLUTION OF HERPES SIMPLEX VIRUS 1 HYPOTHESIS OF ALZHEIMER’S DISEASE CAUSATION

The concept of effects of HSV-1 in AD was first proposed more than thirty years ago [63]. HSV-1 emerged as a likely candidate virus due to a very rare but extremely serious and acute infection of herpes simplex encephalitis (HSE) in the CNS, where the earliest and most severe regions showed pathological changes similar to AD [63]. The neuropathological changes corresponding to the hippocampus and mesial temporal cortex are associated with long-term inflammation both in animal models and in human HSE survivors [64]. HSV-1 DNA resided in latent form in a high proportion of elderly brains from both normals and AD patients. In contrast, HSV-1 infections were present in only a small proportion of brains of AD patients and elderly normals [65 –68]. Viral DNA was present in only a very small proportion of pediatric and brains of the young, in contrast with the high frequency of HSV-1 DNA found in elderly brains [69]. HSV-1 DNA co-localized strongly with amyloid plaques in AD brains but not in normal brains [70]. Further, HSV-1 might recurrently reactivate in brain and subsequently may cause a productive infection, leading to severe damage, cell death, and eventually to the development of AD [71 –73]. Infections with microbes like bacteria and spirochetes, which generate nitric oxide, free radicals, and further induction of apoptosis as proinflammatory cytokine activators, may be considered as a risk factor to cognitive changes or pathophysiological changes of AD [74]. The infections of other viruses like the measles virus and HIV implicated in neurological disease can result in subacute sclerosing panencephalitis [75]. HIV-associated dementia [76 –79] were associated with the formation of characteristic pathological features in AD, including NFTs, phosphorylated tau protein, and neurodegeneration in brain [80].

CHARACTERISTICS OF HSV-1 INFECTION IN BRAIN

Structural advantages facilitating HSV-1 entry into the host cell and into relevant regions of AD

HSV-1 is an enveloped virus surrounded by an icosahedral shaped nucleocapsid, composed of a 152 kB core double-stranded DNA genome [81]. The viral envelope is composed of a lipid bilayer decorated with various glycoproteins. Viral glycoprotein B (gB) and glycoprotein C (gC) participate in attachment of virus to the receptor for heparin sulfate proteoglycan (HSPG) in the host cell. It has been identified as necessary for viral entry into the host cell via host cellular receptor protein interaction with HSV-1 glycoproteins, including gB, gD, gH, and gL [82]. HSV-1 gB had a significant homologous region in common with Aβ and interacted with lipoproteins, particularly APOE protein which may stimulate molecular interaction and further neurodegeneration [83]. The data supports the conclusion that the peptide of gB could emerge as a potent initiator for the cascade of fibril formation and deposition of Aβ if cleaved appropriately, and suggests a link between gB and APOE [84]. HSV-1 viral envelope gD interacts with herpesvirus entry as a mediator when the viral envelope fuses into the host cell membrane [85]. The tegument, located between the viral envelope and the capsid, contains 26 viral proteins. These proteins are relevant to the HSV viral lifecycle, including transporting viral DNA to the nucleus of the host cell, transcripting viral genes, and overturning a variety of host cellular processes [82]. After the virus fuses to the host cell, nucleocapsid and tegument proteins enter the host cytoplasm. The nucleocapsid leaves from cytoplasm to the nucleus, wherein viral DNA is separated and circularizes. A specific tegument protein blocks off host cell protein synthesis [86].

During latency, when HSV-1 occurs reactivation in the trigeminal ganglion (TG), anterograde transport of HSV-1 particles can cause orofacial lesions [87]. Retrograde transport of viral particles between axons can facilitate entry into the locus coeruleus and thus infiltrate into the temporal lobe, especially the entorhinal cortex and hippocampus [87]. HSV-1 infection progressed from the nose to the TG and then reemerged in the facial skin [88]. Blood monocytes infiltrated into the CNS after intranasally infecting mice with a sub-lethal dose of HSV-1 during experimental herpes simplex virus encephalitis [89]. HSV could transmit in the anterograde direction from olfactory receptor neurons to mitral cell neurons in the OB and could extend to amygdala, hippocampus, and the entorhinal cortex [90]. The OB connection to the entorhinal cortex and the entorhinal cortex itself show neurodegeneration characteristic of AD pathology at an early age [91 –93]. HSV-1 DNA was detected from almost all olfactory and trigeminal ganglia of postmortem tissue samples in HSV-1-infected patients [94]. In 90% of all patients diagnosed antemortem with clinical AD, HSV-1 DNA was identified in the TG [95]. Following intranasal administration of HSV-1 to the 17Syn+strain of BALB/c mice, inflammatory cells including macrophages, lymphocytes, neutrophils, and plasma cells, were confirmed via immunochemical antibodies reactive to Mac2 from macrophages, CD3 from T lymphocytes, and myeloperoxidase from neutrophils [96]. During the chronic phase, the presence of microglial activation seems to persist in the damaged area. These cells intensely immunostain with Mac2, known to be a marker upregulated in macrophages participating in phagocytosis [64]. Further, the Morris water maze test, used to detect spatial memory ability, showed deficits in BALB/c mice [96]. This spatial memory deficit seen in HSV-1 infected mice might be similar to the spatial disorientation observed in early-stage AD patients [96]. The molecular logic of vomeronasal organ ligand detection was better understood due to functional expression of vomeronasal receptors which deciphered the neural mechanisms controlling behavior in herpes virus-based amplicon delivery system [97]. In subepithelial myeloid cells, HSV-1 spread from the olfactory epithelium to TG neurons [98]. Further, HSV-1 entered the tree shrew brain following ocular inoculation and HSV-1 transcripts were detected during acute infection [99]. The aforementioned animal studies and others, support the entry of HSV-1 into the brain through the olfactory bulb [100], structures of the limbic system along nerve pathways including the entorhinal cortex and hippocampus, i.e., structures adversely impacted in AD [101]. Clinical olfactory function impairment is connected with increased incidence of MCI and AD [102 –104].

Lifecycle of HSV-1 in viral infections

Viral latency has been established in the TG of the peripheral nervous system (PNS) after initial infection. Life-long HSV-1 infection escapes from the immune system in host cells [105]. HSV-1 infections appear to undergo subclinical and clinical reactivation, including keratitis, recurring oral ulcers and severe encephalitis [106]. The virus has both a latent and productive lifecycle. During the productive lifecycle, the presence of newly produced virions can cause host cell death. Viral genes, such as α-genes (immediate-early), β-genes (early), or γ-genes (late), respectively express α proteins to modulate the viral genome, β-proteins to participate in DNA synthesis of virus, and γ-proteins to emerge as viral structural proteins [86, 107]. During the latent lifecycle, the viral genome exists with no formed virus and the expression of viral gene ceases in the host cell, except for latency-associated transcripts termed LATs facilitating the latency and inhibiting host cellular apoptosis [105].

The weight-of-evidence suggests that HSV-1 reactivation occurs in merely a small number of neurons infected in latency during reactivation phase [108]. Periodic viral reactivation during the latent lifecycle could be induced by diseases, immunodeficiency, and other stressors [109]. HSV-1-infected reactivation was detected in explant cultures of brain tissue in mice, suggesting that mice might be an appropriate animal model for future viral studies [110, 111]. Massive doses of immunosuppressive drugs and radiation in HSV-1-infected mice influenced viral reactivation in vivo. However, the latent reactivation of virus could not be found from brains in explant cultured mice with HSV-1 infection [112]. T cell immune system impairment associated with age is identified as immunosenescence, and is related to increased peripheral reactivation from infected herpes virus including HSV-1 in elderly people [113 –115]. Early neurodegeneration and neuroinflammation are found in the cerebral cortices and trigeminal ganglia of mice after reactivation of HSV-1 from latency [116]. An immune response, mediated by CD8⁺ T lymphocytes infiltrates mouse and human HSV-1-infected TG ganglia. This immune response is in part mediated by secretion of IFN-γ, and suppresses reactivation of virus in infected trigeminal ganglion during latency [117, 118].

ROLE OF HERPESVIRIDAE FAMILY (EXCEPT HSV-1) ALONE OR IN CONCERT WITH APOEɛ4 IN DEVELOPMENT OF AD

Infectious agents, such as HSV-2 and cytomegalovirus (CMV), have been examined for associations with cognitive decline and AD by increasing Aβ production [119 –122] and evoking tau phosphorylation [123, 124]. Furthermore, spirochetes and Chlamydophila pneumonia (C. pneumoniae) might evade the host immune response thereby achieving high burdens in the brains of AD patients. In vitro studies and animal models suggest that this brain burden could induce formation of P-tau and amyloid plaques [125 –129]. In aged APP/PS1 mice, respiratory infection exacerbated Aβ pathology and increased glial activation, suggesting an adverse effect on peripheral regions of AD [130]. Human astrocytoma cells were bound by C. pneumoniae elementary bodies, with the APOE ɛ4 having 3-fold higher levels than cells bearing the non-APOE4 allele [131]. This result suggests that attachment of C. pneumoniae elementary bodies to target host cells is enhanced by APOE4 expression.

Human herpesvirus 6 (HHV6) and HHV7, in a manner similar to HSV-1, were present in elderly normals and AD brains, with AD levels significantly higher than the control groups [132, 133]. Studies by others had shown that HHV6 worsened the damage caused by APOE ɛ4 in AD and HSV-1 in cell cultures and animal tissue [134, 135]. The proportion of HHV6 present in AD patients was high, while the proportion in age-matched normal controls was significantly lower than in patients with HSV-1 [135]. HHV-6A infection was found to enhance APOE ɛ4 mRNA synthesis with a time dependent correlation, indicating that the increased production in HHV-6A RNA correlated to the enhancement in APOE ɛ4 mRNA [136]. APOE4 expression by APOE ɛ4 allele was observed to be upmodulated by HHV-6A infection [137] and protein kinase A (PKA) activity was increased by APOE and in a PKA-dependent pathway the secretion of APOE is operational [138]. Stronger specific humoral responses with HSV-1 infections correlate with protection of cortical volumes and AD conversion, reinforcing the hypothesis referring to a role for HSV-1 in AD pathogenesis [139].

HSV-1 AS A PREDISPOSING FACTOR FOR THE DEVELOPMENT OF AD

Location of HSV-1 in AD-related amyloid plaques and antiviral functions of Aβ peptide

In AD brains, 72% of HSV-1 DNA was associated with plaques and 90% of the plaques contained the viral DNA [140]. In aged normal brains, only 24% of the viral DNA was found, with a lower frequency to amyloid plaques although 80% of plaques contained HSV-1 DNA [140]. These results suggest that viral infection was a major cause resulting in amyloid plaques and thus is probably significant in AD. HSV-1-infected neurons in vitro display tau protein hyperphosphorylation [141]. Specific sites of P-tau inhibiting Aβ toxicity might relate to Aβ antiviral action. Abnormal P-tau presumably caused by HSV-1 infection might produce aggregated Aβ based on anatomic considerations [142 –144]. HSV-1 infection in SH-SY5Y cells and cortical neurons of rat activates amyloidogenic pathways of the host cell, causing multiple AβPP cleavages with accumulation of secreted intracellular and extracellular Aβ_1–40, Aβ_1–42, and additional neurotoxic fragments of AβPP [145]. AβPP level could be reduced in HSV-1-infected neuronal cells [146].

The Aβ peptide has been identified as playing a role in the formation of amyloid plaque and defense against multiple microbes [147 –149]. Amyloid acts protectively by encapsulating pathogens—a once heretical notion that was either ignored or derided [150]. Moreover, studies have found that HHV6 and HSV-1 can induce the production of amyloid plaque after 24–48 hours of infection in mice, and that Aβ oligomers attenuate HSV-1 infection in models of 3-D neural cell culture from human, and protect from acute viral encephalitis in 5×FAD transgenic mice [151, 152]. They also indicated that Aβ can inhibit infection in brain cells and accelerate amyloid fibrilization [151, 152]. While evidence suggests an association of herpesvirus with AD, causation has been difficult to establish [153].

Antiviral activity of IFNs relevant to HSV-1-infected patients in AD

The cytokines including interferons (IFNs) could inhibit infection caused by HSV-1, stimulate the immune system, and activate pathways of neuroinflammation modulated by T-cells particularly [154]. However, IFN treatment adversely affected mood transiently over the first months, while the placebo with antidepressant effect might counterbalance the reduction in cognitive decline rate [155]. IFN and IFN-β1a inducing cognitive decline rate reduction appeared to be well tolerated and safe in AD patients at early phase [155]. Mounting evidence suggests that the antiviral action of IFN displays a beneficial effect in AD patients by its anti-proliferative and immunomodulatory properties. IFNs showed potential efficacy via blocking latent HSV-1 reactivation in a later study [156]. The function of IFN has been identified in TG cell cultures infected by HSV-1 by treating with supernatant enriched with IFNs [157]. Transgene expression in HSV-1-infected TG cells with IFN-β or IFN-γ in explant culture suppressed and delayed reactivation of HSV-1 [154]. Several other studies have identified that IFN-β and IFN-γ have similar effects on blocking HSV-1 replication in immunocompetent mice and cell culture [158 –160]. IFN-λ, a key cytokine participating in innate antiviral defenses, has a particularly perceptible antiviral activity in HSV-1-infected individuals [161]. HSV-1-seropositivity measurements showed that INF-λ serum concentration and anti-HSV-1 antibody titers were higher in MCI individuals and AD than in healthy controls [161].

HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production, associated with IL-6, cGAS, UL37, and RIG-I

Subacute and acute inflammatory responses induced by HSE in humans were mediated by interleukin 6 (IL-6), IFN-γ, and tumor necrosis factor-α (TNF-α) [162]. Elevated IL-6 in the CNS of mice has been found in association with cerebral neurodegeneration thought to be caused by over expression of IL-6 near amyloid plaques [163]. Mouse trigeminal ganglia infected by HSV-1 led to expression of major histocompatibility complex II antigens and increased pro-inflammatory cytokines TNF-α, IFN-γ, and IL-6 [164, 165]. Cyclic GMP-AMP (cGAMP) synthase (cGAS) can function as a DNA sensor. It plays an essential role in catalyzing cGAMP synthesis, detecting cytosol double-stranded (ds) DNA, and inducing IFNs and inflammatory cytokines [166, 167]. Mouse or human cGAS deamidated by UL37 promotes lytic replication of HSV-1, indicating that viral pathogen uses variations from natural sequence of innate immune components to destroy host defenses [168].

Murine gamma herpesvirus 68, one of the gamma herpesviruses similar to human Kaposi’s sarcoma-associated herpesvirus, evades host cytokine production [169, 170]. Site-specific deamidation of retinoic acid-induced gene I (RIG-I) in the helicase 2i domain was characterized by impaired ATP hydrolysis and RNA detection of RIG-I [171]. RIG-I induced by HSV-1 prevents RIG-I activation through sensing viral ds RNA and inhibits production of antiviral cytokine, thereby increasing HSV-1 replication [171, 172]. The UL37 as a protein deamidase, targets RIG-I to block activation induced by RNA and its tegument protein was sufficient for deamidation of RIG-I in vitro, suggesting the role of deamidation of viral protein in immune regulation [173]. The cytosolic RIG-I receptor, a genuine RNA sensor response to infection of virus, activates interferon regulatory factor 3 and nuclear factor κB by the mitochondrial antiviral signaling protein [174 –176].

IB along with CMV or HSV-1 associated with cognitive decline and AD

The first study on total infectious burden (IB), as systemic microbial burden, investigated 383 home-dwelling individuals and found a history of stroke or coronary heart disease, and 18% had type 2 diabetes [177]. Viral IB, a composite serological measure of serum antibody levels correlated to common pathogens such as CMV and HSV-1, leads to stroke [178] and cardiovascular diseases and is associated with cognitive decline in epidemiological studies [179, 180]. IB and cognitive decline by using a composite serologic measure detect exposure to both viral pathogens (HSV-1, HSV2, and CMV) and bacterial (Helicobacter pylori and C. pneumoniae) [180]. The elevation of IB may increase Aβ levels directly and subsequently cause AD development. Cell culture production of Aβ increased by HSV-1 infection by upregulating β- and γ-secretase levels, suggests that Aβ is a pore-forming antimicrobial peptide [181, 182]. In a previous study, bacterial IB showed no connection with cognitive impairment [183]. Adjusted for age, gender, education, APOE genotype, and other comorbidities, AD-associated higher total IB, viral IB (CMV and HSV-1), and bacterial IB (C. pneumoniae), supports a role for infection and inflammation in the etiology of AD [184]. Rates of positivity for HSV-1 in older Blacks and Whites were much lower than for CMV [185]. It indicates that CMV but not HSV-1 increases more risk of AD, highlighting that another vital factor is assay sensitivity. The protein expression from infections of common pathogens had significant AβPP and Aβ homology [186, 187]. This expression of proteins may trigger autoantibodies with cross reaction to AβPP bound with membrane, cause neuronal and synaptic dysfunction, and final cognitive decline [186, 187]. IB index of weighting risk of quantitative stroke was inversely related to cognitive decline of memory domain and executive function from baseline, suggesting that common infections with subsequent inflammatory responses interact with vascular damage, neurodegeneration, and aging [188].

ASSOCIATION OF HSV-1 INFECTION WITH CARRIAGE OF THE APOEɛ4 GENE

Studies measuring HSV-1 DNA from brain or HSV-1 antibody serology showed that the risk of AD was significantly increased by infection with HSV-1 alone and in concert with the APOE ɛ4 [66]. AD risk-associated genes emerged as transcriptional regulators such as Gamma-secretase Subunit Presenilin-1, Beta-Site APP Cleaving Enzyme 1, Clusterin, and Phosphatidylinositol Binding Clathrin Assembly Protein could be altered by viral infection [189]. It should be noted that virus in brain of carriers of the APOE ɛ4 allele, accounting for 60% of cases, confers a strong risk factor for AD [190]. The presence of the HSV-1 genome in the brain plus the possession of APOE ɛ4 shows more risk toward developing AD relative to the carriage of APOE ɛ4 alone [191, 192]. Furthermore, APOE has been found to modulate susceptibility to microbial infections caused by HSV-1 and HSV-2, e.g., herpes labiali and genital herpes [190, 193].

Different APOE isoforms influence the susceptibility and outcome of several diseases caused by viral infections [194]. APOE protein interacts directly with purified gB from HSV-1 [195] and accumulations of both APOE and HSV-1 inside the cells result from cellular entry via an HSPG receptor [196]. During acute infection, APOE4 was more efficient than APOE3 in promoting HSV-1 colonization of the brain by attaching to HSPG, and may increase susceptibility to processes of neurodegeneration connected to the APOE ɛ4 gene [197, 198]. Variation at the APOE locus may be connected with clinical manifestations of HSV-1 infection, whereas APOE subtype does not appear to associate with herpes simplex viral reactivation in humans [199]. The evidence proved that patients with frequent recurrent herpes labialis carried APOE ɛ4 more often than HSV-1 seropositive individuals who did not experience recurrences of the disease [44, 200].

In a large population-based cohort study, carriage of HSV showed significant association with declining episodic memory function, especially among APOE ɛ4 carriers both in cross-sectional and longitudinal results [201]. HSV-1-seropositive APOE ɛ4 also shows connection with cognitive impairment in age-adjusted cardiovascular patients [202]. When the immune system declines, HSV-1 reaches the brain in aging and resides there in latency, and reactivates upon stress or immunosuppression in the PNS. Reactivation can lead to an acute but localized infection, which can be more serious in an APOE4 carrier [203].

APOE ɛ4 is associated with the HSV lifecycle by involvement in viral infectivity [204]. Furthermore, APOE in the lifecycle of HSV-1 is related to abnormal autophagy in AD [205]. Acute hematogenous HSV-1 infection in a murine model showed that viral neuroinvasion was reduced in APOE gene knockout mice compared to wild-type mice and that the APOE dose was directly associated with the concentration of HSV-1 DNA [206]. APOE ɛ4 can modulate expression of HSV-1 gene or its spread in the brain by utilizing transgenic mice expressing ɛ2, ɛ3, and ɛ4 genotype of APOE gene in astrocytes from the glial fibrillary acidic protein promoter [207]. APOE ɛ4 acting in concert with HSV-1 in AD brains might lead to Aβ accumulation and AD-like tau, causing amyloid plaques and NFTs, and eventually to AD [208]. In genome-wide association study datasets, AD genes are increased to reflect pathogen diversity and pathogen resistance of implied earlier infection prior to the older ages of AD patients [209]. Wild-type APOE+/+mice infected with HSV-1 peripherally had 13.7 times the concentrations of HSV-1 DNA in brain than mice lacking APOE infected by HSV-1 [210].

CONCLUSION

HSV-1 DNA infection in brain alone or in concert with the APOE ɛ4 allele increased the risk of AD and aggravated the pathogenesis of AD. APOE protein, encoded by the APOE gene, has different structural domains and functional isoforms, which may contribute to a differential role of APOE polymorphisms in AD. APOE ɛ4 is a genetic variant for increased risk in AD compared to APOE ɛ2 and APOE ɛ3. APOE ɛ4 connected with AD plays a role in neuron-associated functions, inflammatory responses and pathological changes. The involvement of APOE ɛ4 elevated risk to hippocampal volume loss, cognitive impairment and AD-associated Aβ deposition is greater in women than men, and HT attenuated the risk of dementia linked with APOE ɛ4 genotype. Conversely, APOE ɛ4 was an ancestral genotype, which shows protective effects on fertility and reproduction, lowers the risk of intracranial aneurysms and shows improved mental performance in youth. It is obvious that HSV-1 exerts a strong influence in AD as the hypothesis has been proposed. HSV-1 enters into the host cell and goes into trigeminal ganglia, hippocampus, and so on, although animal and cell models are limited to systematically illuminate effects of HSV-1 propagation on AD. HSV-1 lifecycle goes through a relatively long incubation period. HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production in AD. IFNs have antiviral activity of HSV-1-infected AD patients. HSV-1 shows connection with IB in cognitive decline and AD. However, HSV-1 with ɛ4 gene variant of APOE was examined to associate with abnormal autophagy, higher concentrations of HSV-1 DNA in AD and formation of pathological features of AD, involving amyloid plaques and NFTs. The construction of new types of animal models combined with HSV-1 and APOE ɛ4 may prove beneficial in understanding the etiology of AD, although not yet developed.

Footnotes

ACKNOWLEDGMENTS

We sincerely thank the contributions and hard work of all the researchers and experts who provided data support. Initiation of the work by Professor Feng-xue Lao and Ying-hui Shang of Beijing Union University are acknowledged.

Financial support from the National Natural Science Foundation of China (31471587), Ten Frontier Research Directions of Discipline Orientation (ZK40201902) and Graduate Funding Project of Beijing Union University are gratefully acknowledged.

Authors’ disclosures available online ().

References

Jorm

, Jolley

(1998) The incidence of dementia: A meta-analysis. Neurology 51, 728–733.

Mayeux

, Stern

(2012) Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med 2, a006239.

Jack

Jr , Bennett

, Blennow

, Carrillo

, Dunn

, Haeberlein

, Holtzman

, Jagust

, Jessen

, Karlawish

, Liu

, Molinuevo

, Montine

, Phelps

, Rankin

, Rowe

, Scheltens

, Siemers

, Snyder

, Sperling

(2018) NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14, 535–562.

Long

, Holtzman

(2019) Alzheimer disease: An update on pathobiology and treatment strategies. Cell 179, 312–339.

Alonso Vilatela

, Lopez-Lopez

, Yescas-Gomez

(2012) Genetics of Alzheimer’s disease. Arch Med Res 43, 622–631.

Naj

, Schellenberg

(2017) Genomic variants, genes, and pathways of Alzheimer’s disease: An overview. Am J Med Genet B Neuropsychiatr Genet 174, 5–26.

Trommer

, Shah

, Yun

, Gamkrelidze

, Pasternak

, Ye

, Sotak

, Sullivan

, Pasternak

, Ladu

(2004) ApoE isoform affects LTP in human targeted replacement mice. Neuroreport 15, 2655–2658.

Bellosta

, Nathan

, Orth

, Dong

, Mahley

, Pitas

(1995) Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J Biol Chem 270, 27063–27071.

Gibson

, Haroutunian

, Zhang

, Park

, Shi

, Lesser

, Mohs

, Sheu

, Blass

(2010) Mitochondrial damage in Alzheimer’s disease varies with apolipoprotein E genotype. Ann Neurol 48, 297–303.

10.

Leoni

, Solomon

, Kivipelto

(2010) Links between ApoE, brain cholesterol metabolism, tau and amyloid beta-peptide in patients with cognitive impairment. Biochem Soc Trans 38, 1021–1025.

11.

Payami

, Zareparsi

, Montee

, Sexton

, Kaye

, Bird

, Yu

, Wijsman

, Heston

, Litt

, Schellenberg

(1996) Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: A possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet 58, 803–811.

12.

Bretsky

, Buckwalter

, Seeman

, Miller

, Poirier

, Schellenberg

, Finch

, Henderson

(1999) Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease. Alzheimer Dis Assoc Disord 13, 216–221.

13.

Jamieson

, Maitland

, Wilcock

, Craske

, Itzhaki

(1991) Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33, 224–227.

14.

Agostini

, Mancuso

, Hernis

, Costa

, Nemni

, Clerici

(2018) HSV-1-specific IgG subclasses distribution and serum neutralizing activity in Alzheimer’s disease and in mild cognitive impairment. J Alzheimers Dis 63, 131–138.

15.

Organization

(2020) Herpes simplex virus. World Health Organization, https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus, Last updated May 1, 2020, Accessed on June 6, 2020.

16.

Santana

, Recuero

, Bullido

, Valdivieso

, Aldudo

(2012) Herpes simplex virus type I induces the accumulation of intracellular beta-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. Neurobiol Aging 33, 430.e419–433.

17.

Santana

, Sastre

, Recuero

, Bullido

, Aldudo

(2013) Oxidative stress enhances neurodegeneration markers induced by herpes simplex virus type 1 infection in human neuroblastoma cells. PLoS One 8, e75842.

18.

Menendez

, Carr

DJJ

(2017) Herpes simplex virus-1 infects the olfactory bulb shortly following ocular infection and exhibits a long-term inflammatory profile in the form of effector and HSV-1-specific T cells. J Neuroinflammation 14, 124.

19.

Devanand

(2018) Viral hypothesis and antiviral treatment in Alzheimer’s disease. Curr Neurol Neurosci Rep 18, 55.

20.

Letenneur

, Peres

, Fleury

, Garrigue

, Barberger-Gateau

, Helmer

, Orgogozo

, Gauthier

, Dartigues

(2008) Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: A population-based cohort study. PLoS One 3, e3637.

21.

Kobayashi

, Nagata

, Shinagawa

, Oka

, Shimada

, Shimizu

, Tatebayashi

, Yamada

, Nakayama

, Kondo

(2013) Increase in the IgG avidity index due to herpes simplex virus type 1 reactivation and its relationship with cognitive function in amnestic mild cognitive impairment and Alzheimer’s disease. Biochem Biophys Res Commun 430, 907–911.

22.

Roses

(1996) Apolipoprotein E alleles as risk factors in Alzheimer’s Disease. Annu Rev Med 47, 387–400.

23.

Mahley

, Rall

(2000) Apolipoprotein E: Far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1, 507–537.

24.

Berr

(1995) [Apolipoprotein E and Alzheimer disease]. Lancet 151, 3–5.

25.

Weisgraber

, Mahley

(1996) Human apolipoprotein E: The Alzheimer’s disease connection. FASEB J 10, 1485–1494.

26.

Hatters

, Peters-Libeu

, Weisgraber

(2006) Apolipoprotein E structure: Insights into function. Trends Biochem Sci 31, 445–454.

27.

Frieden

(2015) ApoE: The role of conserved residues in defining function. Protein Sci 24, 138–144.

28.

Dobson

, Sales

, Hoggard

, Wozniak

, Crutcher

(2006) The receptor-binding region of human apolipoprotein E has direct anti-infective activity. J Infect Dis 193, 442–450.

29.

Mahley

, Weisgraber

, Huang

(2006) Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A 103, 5644–5651.

30.

Tudorache

, Trusca

, Gafencu

(2017) Apolipoprotein E - A multifunctional protein with implications in various pathologies as a result of its structural features. Comput Struct Biotechnol J 15, 359–365.

31.

Verghese

, Castellano

, Holtzman

(2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10, 241–252.

32.

Lebedeva

, Sakovich

, Khusainova

, Kutuev

, Valiev

, Khusnutdinova

(2007) [The role of angiotensin-converting enzyme and apolipoprotein E in the development of intracranial aneurysms.]. Zh Nevrol Psikhiatr Im S S Korsakova 107, 52–57.

33.

Badrnya

, Doherty

, Richardson

, McConnell

, Lamont

, Veitinger

, FitzGerald

, Zellner

, Umlauf

(2018) Development of a new biochip array for APOE4 classification from plasma samples using immunoassay-based methods. Clin Chem Lab Med 56, 796–802.

34.

Castellano

, Kim

, Stewart

, Jiang

, DeMattos

, Patterson

, Fagan

, Morris

, Mawuenyega

, Cruchaga

(2011) Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 3, 89ra5789ra57.

35.

Bales

, Dodart

, DeMattos

, Holtzman

, Paul

(2002) Apolipoprotein E, amyloid, and Alzheimer disease. Mol Interv 2, 363.

36.

Farrer

, Cupples

, Haines

, Hyman

, Kukull

, Mayeux

, Myers

, Pericak-Vance

, Risch

, Van Duijn

(1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: A meta-analysis. JAMA 278, 1349–1356.

37.

Rubinsztein

, Easton

(1999) Apolipoprotein E genetic variation and Alzheimer’s disease. Dement Geriatr Cogn Disord 10, 199–209.

38.

Liu

, Pan

, Zhang

, Shen

, Collins

, Cole

, Koster

, Ben

, Dai

, Zhou

(2015) APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice. Mol Neurodegener 10, 1–17.

39.

Smith

, Ashford

(2017) APOE ɛ4 Allele-associated Alzheimer’s disease risk is consistent with increased lifetime exposure to a neurotoxic process. Dementia 13, 14.

40.

, Jie

, Gutman

, Baxter

, Thompson

, Caselli

, Wang

(2016) Influence of APOE genotype on hippocampal atrophy over time - an N=1925 surface-based ADNI Study. PLoS One 11, e0152901.

41.

Smith

, Ashford

, Perfetti

(2019) Putative survival advantages in young Apolipoprotein epsilon4 carriers are associated with increased neural stress. J Alzheimers Dis 68, 885–923.

42.

Altmann

, Tian

, Henderson

, Greicius

(2014) Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 75, 563–573.

43.

Szoeke

, Goodwill

, Gorelik

, Dennerstein

, Caeyenberghs

, Simpson

, Hill

, Campbell

(2019) Apolipoprotein E4 mediates the association between midlife dyslipidemia and cerebral amyloid in aging women. J Alzheimers Dis 68, 105–114.

44.

Kunzler

, Youmans

, Yu

, Ladu

, Tai

(2014) APOE modulates the effect of estrogen therapy on Abeta accumulation EFAD-Tg mice. Neurosci Lett 560, 131–136.

45.

Ryan

, Carriere

, Scali

, Dartigues

, Tzourio

, Poncet

, Ritchie

, Ancelin

(2009) Characteristics of hormone therapy, cognitive function, and dementia: The prospective 3C Study. Neurology 73, 1729–1737.

46.

Kang

, Grodstein

(2012) Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiol Aging 33, 1129–1137.

47.

Valen-Sendstad

, Engedal

, Stray-Pedersen

, Strobel

, Barnett

, Nurminemi

, Meyer

(2010) Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: A 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone. Am J Geriatr Psychiatry 18, 11–20.

48.

Yaffe

, Haan

, Byers

, Tangen

, Kuller

(2000) Estrogen use, APOE, and cognitive decline: Evidence of gene–environment interaction. Neurology 54, 1949–1954.

49.

Kang

, Weuve

, Grodstein

(2004) Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology 63, 101–107.

50.

Jacobs

, Kroenke

, Lin

, Epel

, Kenna

, Blackburn

, Rasgon

(2013) Accelerated cell aging in female APOE-ɛ4 carriers: Implications for hormone therapy use. PLoS One 8, e54713.

51.

Huebbe

, Rimbach

(2017) Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors. Ageing Res Rev 37, 146–161.

52.

Itzhaki

, Dobson

, Wozniak

(2004) Herpes simplex virus type 1 and Alzheimer’s disease. Ann Neurol 55, 300–301.

53.

van Exel

, Koopman

, van Bodegom

, Meij

, de Knijff

, Ziem

, Finch

, Westendorp

(2017) Effect of APOE ɛ4 allele on survival and fertility in an adverse environment. PloS One 12, e0179497.

54.

Gerdes

, Gerdes

, Hansen

, Klausen

, Faergeman

(1996) Are men carrying the apolipoprotein epsilon 4- or epsilon 2 allele less fertile than epsilon 3 epsilon 3 genotypes? Hum Genet 98, 239–242.

55.

Limongi

, Baldelli

(2016) Redox imbalance and viral infections in neurodegenerative diseases. Oxid Med Cell Longev 2016, 6547248.

56.

Mueller

, Fischer

, Gessner

, Rosendahl

, Bohm

, van Bommel

, Knop

, Sarrazin

, Witt

, Marques

, Kovacs

, Schleinitz

, Stumvoll

, Bluher

, Bugert

, Schott

, Berg

(2016) Apolipoprotein E allele frequencies in chronic and self-limited hepatitis C suggest a protective effect of APOE4 in the course of hepatitis C virus infection. Liver Int 36, 1267–1274.

57.

Fabris

, Toniutto

, Bitetto

, Minisini

, Smirne

, Caldato

, Pirisi

(2005) Low fibrosis progression of recurrent hepatitis C in apolipoprotein E epsilon4 carriers: Relationship with the blood lipid profile. Liver Int 25, 1128–1135.

58.

Puttonen

, Elovainio

, Kivimaki

, Lehtimaki

, Keltikangas-Jarvinen

(2003) The combined effects of apolipoprotein E polymorphism and low-density lipoprotein cholesterol on cognitive performance in young adults. Neuropsychobiology 48, 35–40.

59.

Jochemsen

, Muller

, van der Graaf

, Geerlings

(2012) APOE ɛ4 differentially influences change in memory performance depending on age. The SMART-MR study. Neurobiol Aging 33, 832.e815–832.e822.

60.

Acevedo

, Piper

, Craytor

, Benice

, Raber

(2010) Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children. Pediatr Res 67, 293.

61.

Stening

, Persson

, Eriksson

, Wahlund

L-O

, Zetterberg

, Söderlund

(2017) Specific patterns of whole-brain structural covariance of the anterior and posterior hippocampus in young APOE ɛ4 carriers. Behav Brain Res 326, 256–264.

62.

Stening

, Persson

, Eriksson

, Wahlund

L-O

, Zetterberg

, Söderlund

(2016) Apolipoprotein E ɛ4 is positively related to spatial performance but unrelated to hippocampal volume in healthy young adults. Behav Brain Res 299, 11–18.

63.

Ball

(1982) Limbic predilection in Alzheimer dementia: Is reactivated herpesvirus involved? Can J Neurol Sci 9, 303–306.

64.

Armien

, Hu

, Little

, Robinson

, Lokensgard

, Low

, Cheeran

(2010) Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis. Brain Pathol 20, 738–750.

65.

Olsson

, Lovheim

, Honkala

, Karhunen

, Elgh

, Kok

(2016) HSV presence in brains of individuals without dementia: The TASTY brain series. Dis Model Mech 9, 1349–1355.

66.

Steel

, Eslick

(2015) Herpes viruses increase the risk of Alzheimer’s disease: A meta-analysis. J Alzheimers Dis 47, 351–364.

67.

Lovheim

, Gilthorpe

, Adolfsson

, Nilsson

, Elgh

(2015) Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement 11, 593–599.

68.

Agostini

, Mancuso

, Baglio

, Cabinio

, Hernis

, Costa

, Calabrese

, Nemni

, Clerici

(2016) High avidity HSV-1 antibodies correlate with absence of amnestic Mild Cognitive Impairment conversion to Alzheimer’s disease. Brain Behav Immun 58, 254–260.

69.

Wozniak

, Shipley

, Combrinck

, Wilcock

, Itzhaki

(2005) Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer’s disease patients. J Med Virol 75, 300–306.

70.

Wozniak

, Mee

, Itzhaki

(2009) Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques. J Pathol 217, 131–138.

71.

Fine

, Sorbello

, Kortepeter

, Scarazzini

(2013) Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis 57, 849–852.

72.

Itzhaki

(2014) Herpes simplex virus type 1 and Alzheimer’s disease: Increasing evidence for a major role of the virus. Front Aging Neurosci 6, 202.

73.

Itzhaki

, Cosby

, Wozniak

(2008) Herpes simplex virus type 1 and Alzheimer’s disease: The autophagy connection. J Neurovirol 14, 1–4.

74.

Bibi

, Yasir

, Sohrab

, Azhar

, Al-Qahtani

, Abuzenadah

, Kamal

, Naseer

(2014) Link between chronic bacterial inflammation and Alzheimer disease. CNS Neurol Disord Drug Targets 13, 1140–1147.

75.

McQuaid

, Allen

, McMahon

, Kirk

(1994) Association of measles virus with neurofibrillary tangles in subacute sclerosing panencephalitis: A combined hybridization and immunocytochemical investigation. Neuropathol Appl Neurobiol 20, 103–110.

76.

Soontornniyomkij

, Moore

, Gouaux

, Soontornniyomkij

, Tatro

, Umlauf

, Masliah

, Levine

, Singer

, Vinters

(2012) Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ɛ4 carriers. AIDS 26, 2327.

77.

Mocchetti

, Bachis

, Esposito

, Turner

, Taraballi

, Tasciotti

, Paige

, Avdoshina

(2014) Human immunodeficiency virus-associated dementia: A link between accumulation of viral proteins and neuronal degeneration. Curr Trends Neurol 8, 71–85.

78.

Anthony

, Ramage

, Carnie

, Simmonds

, Bell

(2006) Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy. Acta Neuropathol 111, 529–538.

79.

Brown

, Scarola

, Smith

, Sanberg

, Tan

, Giunta

(2014) The role of tau protein in HIV-associated neurocognitive disorders. Mol Neurodegener 9, 40.

80.

Harris

, Harris

, Mancuso

(2015) Herpes simplex virus type 1 and other pathogens are key causative factors in sporadic Alzheimer’s disease. J Alzheimers Dis 48, 319–353.

81.

Kaye

, Choudhary

(2006) Herpes simplex keratitis. Prog Retin Eye Res 25, 355–380.

82.

Kukhanova

, Korovina

, Kochetkov

(2014) Human herpes simplex virus: Life cycle and development of inhibitors. Biochemistry (Mosc) 79, 1635–1652.

83.

Leissring

, Sugarman

, LaFerla

(1998) Herpes simplex virus infections and Alzheimer’s disease. Implications for drug treatment and immunotherapy. Drugs Aging 13, 193–198.

84.

Cribbs

, Azizeh

, Cotman

, LaFerla

(2000) Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer’s A beta peptide. Biochemistry 39, 5988–5994.

85.

Spear

(2004) Herpes simplex virus: Receptors and ligands for cell entry. Cell Microbiol 6, 401–410.

86.

Itzhaki

, Wozniak

(2006) Herpes simplex virus type 1, apolipoprotein E, and cholesterol: A dangerous liaison in Alzheimer’s disease and other disorders. Prog Lipid Res 45, 73–90.

87.

Steiner

, Kennedy

, Pachner

(2007) The neurotropic herpes viruses: Herpes simplex and varicella-zoster. Lancet Neurol 6, 1015–1028.

88.

Shivkumar

, Milho

, May

, Nicoll

, Efstathiou

, Stevenson

(2013) Herpes simplex virus 1 targets the murine olfactory neuroepithelium for host entry. J Virol 87, 10477–10488.

89.

Menasria

, Canivet

, Piret

, Boivin

(2015) Infiltration pattern of blood monocytes into the central nervous system during experimental herpes simplex virus encephalitis. PLoS One 10, e0145773.

90.

Mori

, Nishiyama

, Yokochi

, Kimura

(2005) Olfactory transmission of neurotropic viruses. J Neurovirol 11, 129–137.

91.

Braak

, Braak

, Bohl

(1993) Staging of Alzheimer-related cortical destruction. Eur Neurol 33, 403–408.

92.

Christen-Zaech

, Kraftsik

, Pillevuit

, Kiraly

, Martins

, Khalili

, Miklossy

(2003) Early olfactory involvement in Alzheimer’s disease. Can J Neurol Sci 30, 20–25.

93.

Kovacs

, Cairns

, Lantos

(2001) Olfactory centres in Alzheimer’s disease: Olfactory bulb is involved in early Braak’s stages. Neuroreport 12, 285–288.

94.

Liedtke

, Opalka

, Zimmermann

, Lignitz

(1993) Age distribution of latent herpes simplex virus 1 and varicella-zoster virus genome in human nervous tissue. J Neurol Sci 116, 6–11.

95.

Hill

, Ball

, Neumann

, Azcuy

, Bhattacharjee

, Bouhanik

, Clement

, Lukiw

, Foster

, Kumar

, Kaufman

, Thompson

(2008) The high prevalence of herpes simplex virus type 1 DNA in human trigeminal ganglia is not a function of age or gender. J Virol 82, 8230–8234.

96.

Ball

, Lukiw

, Kammerman

, Hill

(2013) Intracerebral propagation of Alzheimer’s disease: Strengthening evidence of a herpes simplex virus etiology. Alzheimers Dement 9, 169–175.

97.

Stein

, Alonso

, Zufall

, Leinders-Zufall

, Chamero

(2016) Functional overexpression of vomeronasal receptors using a herpes simplex virus type 1 (HSV-1)-derived amplicon. PLoS One 11, e0156092.

98.

Shivkumar

, Lawler

, Milho

, Stevenson

(2016) Herpes simplex virus 1 interaction with myeloid cells in vivo. J Virol 90, 8661–8672.

99.

, Li

, Wang

, Lang

, Xia

, Fraser

, Gao

, Zhou

(2016) Reactivation of HSV-1 following explant of tree shrew brain. J Neurovirol 22, 293–306.

100.

Baringer

, Pisani

(1994) Herpes simplex virus genome in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol 36, 823–829.

101.

McLean

, Shipley

, Bernstein

, Corbett

(1993) Selective lesions of neural pathways following viral inoculation of the olfactory bulb. Exp Neurol 122, 209–222.

102.

Schubert

, Carmichael

, Murphy

, Klein

, Cruickshanks

(2008) Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults. J Am Geriatr Soc 56, 1517–1521.

103.

Roberts

, Christianson

, Kremers

, Mielke

, Machulda

, Vassilaki

, Alhurani

, Geda

, Knopman

, Petersen

(2016) Association between olfactory dysfunction and amnestic mild cognitive impairment and Alzheimer disease dementia. JAMA Neurol 73, 93–101.

104.

Woodward

, Amrutkar

, Shah

, Benedict

, Rajakrishnan

, Doody

, Yan

, Szigeti

(2017) Validation of olfactory deficit as a biomarker of Alzheimer disease. Neurol Clin Pract 7, 5–14.

105.

Perng

, Jones

(2010) Towards an understanding of the herpes simplex virus type 1 latency-reactivation cycle. Interdiscip Perspect Infect Dis 2010, 262415.

106.

Bearer

(2012) HSV, axonal transport and Alzheimers disease: In vitro and in vivo evidence for causal relationships. Future Virol 7, 885–899.

107.

Pereira

(1996) Herpes simplex: Evolving concepts. J Am Acad Dermatol 35, 503–520; quiz 521-502.

108.

Sawtell

(1998) The probability of in vivo reactivation of herpes simplex virus type 1 increases with the number of latently infected neurons in the ganglia. J Virol 72, 6888–6892.

109.

Held

, Derfuss

(2011) Control of HSV-1 latency in human trigeminal ganglia–current overview. J Neurovirol 17, 518–527.

110.

Chen

, Yao

, Huang

, Hsu

, Lei

, Shiau

, Chen

(2006) Efficient reactivation of latent herpes simplex virus from mouse central nervous system tissues. J Virol 80, 12387–12392.

111.

Yao

, Ling

, Tung

, Hsu

, Chen

(2014) In vivo reactivation of latent herpes simplex virus 1 in mice can occur in the brain before occurring in the trigeminal ganglion. J Virol 88, 11264–11270.

112.

Cabrera

, Wohlenberg

, Openshaw

, Rey-Mendez

, Puga

, Notkins

(1980) Herpes simplex virus DNA sequences in the CNS of latently infected mice. Nature 288, 288–290.

113.

Stowe

, Kozlova

, Yetman

, Walling

, Goodwin

, Glaser

(2007) Chronic herpesvirus reactivation occurs in aging. Exp Gerontol 42, 563–570.

114.

Koch

, Solana

, Dela Rosa

, Pawelec

(2006) Human cytomegalovirus infection and T cell immunosenescence: A mini review. Mech Ageing Dev 127, 538–543.

115.

Stowe

, Peek

, Cutchin

, Goodwin

(2012) Reactivation of herpes simplex virus type 1 is associated with cytomegalovirus and age. J Med Virol 84, 1797–1802.

116.

Martin

, Aguila

, Araya

, Vio

, Valdivia

, Zambrano

, Concha

, Otth

(2014) Inflammatory and neurodegeneration markers during asymptomatic HSV-1 reactivation. J Alzheimers Dis 39, 849–859.

117.

Nicoll

, Proenca

, Efstathiou

(2012) The molecular basis of herpes simplex virus latency. FEMS Microbiol Rev 36, 684–705.

118.

St Leger

, Hendricks

(2011) CD8+T cells patrol HSV-1-infected trigeminal ganglia and prevent viral reactivation. J Neurovirol 17, 528–534.

119.

Kristen

, Santana

, Sastre

, Recuero

, Bullido

, Aldudo

(2015) Herpes simplex virus type 2 infection induces AD-like neurodegeneration markers in human neuroblastoma cells. Neurobiol Aging 36, 2737–2747.

120.

Lurain

, Hanson

, Martinson

, Leurgans

, Landay

, Bennett

, Schneider

(2013) Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J Infect Dis 208, 564–572.

121.

, Ni

, Liu

, Teeling

, Takayama

, Collcutt

, Ibbett

, Nakanishi

(2017) Cathepsin B plays a critical role in inducing Alzheimer’s disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain Behav Immun 65, 350–361.

122.

Wang

, Zeng

, Feng

, Tian

, Liu

, Qiu

, Yan

, Yang

, Xiong

, Zhang

, Wang

, Liu

(2014) Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases beta-amyloid by enhancing expression of presenilin-2. Front Aging Neurosci 6, 66.

123.

Miklossy

(1993) Alzheimer’s disease–a spirochetosis? Neuroreport 4, 1069.

124.

Miklossy

(2016) Bacterial amyloid and DNA are important constituents of senile plaques: Further evidence of the spirochetal and biofilm nature of senile plaques. J Alzheimers Dis 53, 1459–1473.

125.

Balin

, Gerard

, Arking

, Appelt

, Branigan

, Abrams

, Whittum-Hudson

, Hudson

(1998) Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol 187, 23–42.

126.

Miklossy

, Kasas

, Janzer

, Ardizzoni

, Van der Loos

(1994) Further ultrastructural evidence that spirochaetes may play a role in the aetiology of Alzheimer’s disease. Neuroreport 5, 1201–1204.

127.

Miklossy

(2011) Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med 13, e30.

128.

Miklossy

, Kis

, Radenovic

, Miller

, Forro

, Martins

, Reiss

, Darbinian

, Darekar

, Mihaly

, Khalili

(2006) Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging 27, 228–236.

129.

Little

, Hammond

, MacIntyre

, Balin

, Appelt

(2004) Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol Aging 25, 419–429.

130.

McManus

, Higgins

, Mills

, Lynch

(2014) Respiratory infection promotes T cell infiltration and amyloid-beta deposition in APP/PS1 mice. Neurobiol Aging 35, 109–121.

131.

Gerard

, Fomicheva

, Whittum-Hudson

, Hudson

(2008) Apolipoprotein E4 enhances attachment of Chlamydophila (Chlamydia) pneumoniae elementary bodies to host cells. Microb Pathog 44, 279–285.

132.

Jamieson

, Maitland

, Craske

, Wilcock

, Itzhaki

(1991) Detection of herpes simplex virus type 1 DNA sequences in normal and Alzheimer’s disease brain using polymerase chain reaction. Biochem Soc Trans 19, 122s.

133.

Hogestyn

, Mock

, Mayer-Proschel

(2018) Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology. Neural Regen Res 13, 211–221.

134.

Fan

, Cai

, Gao

, Lin

, Huang

, Tang

, Liu

(2017) APOE epsilon4 allele elevates the expressions of inflammatory factors and promotes Alzheimer’s disease progression: A comparative study based on Han and She populations in the Wenzhou area. Brain Res Bull 132, 39–43.

135.

Lin

, Wozniak

, Cooper

, Wilcock

, Itzhaki

(2002) Herpesviruses in brain and Alzheimer’s disease. J Pathol 197, 395–402.

136.

Rizzo

, Bortolotti

, Gentili

, Rotola

, Bolzani

, Caselli

, Tola

, Di Luca

(2019) KIR2DS2/KIR2DL2/HLA-C1 haplotype is associated with Alzheimer’s disease: Implication for the role of herpesvirus infections. J Alzheimers Dis 67, 1379–1389.

137.

Zhu

, Hui

(2003) Apolipoprotein E binding to low density lipoprotein receptor-related protein-1 inhibits cell migration via activation of cAMP-dependent protein kinase A. J Biol Chem 278, 36257–36263.

138.

Kockx

, Guo

, Huby

, Lesnik

, Kay

, Sabaretnam

, Jary

, Hill

, Gaus

, Chapman

, Stow

, Jessup

, Kritharides

(2007) Secretion of apolipoprotein E from macrophages occurs via a protein kinase A and calcium-dependent pathway along the microtubule network. Circ Res 101, 607–616.

139.

Stoykovich

, Gibas

(2019) APOE epsilon4, the door to insulin-resistant dyslipidemia and brain fog? A case study. Alzheimers Dement (Amst) 11, 264–269.

140.

Bouter

, Lopez Noguerola

, Tucholla

, Crespi

, Parker

, Wiltfang

, Miles

, Bayer

(2015) Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol 130, 713–729.

141.

Alvarez

, Aldudo

, Alonso

, Santana

, Valdivieso

(2012) Herpes simplex virus type 1 induces nuclear accumulation of hyperphosphorylated tau in neuronal cells. J Neurosci Res 90, 1020–1029.

142.

Ittner

, Chua

, Bertz

, Volkerling

, van der Hoven

, Gladbach

, Przybyla

, Bi

, van Hummel

, Stevens

, Ippati

, Suh

, Macmillan

, Sutherland

, Kril

, Silva

, Mackay

, Poljak

, Delerue

, Ke

, Ittner

(2016) Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer’s mice. Science 354, 904–908.

143.

White

, Kandel

, Tripathi

, Condon

, Qi

, Taubenberger

, Hartshorn

(2014) Alzheimer’s associated beta-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One 9, e101364.

144.

Braak

, Del Tredici

(2015) The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain 138, 2814–2833.

145.

Harris

, Harris

(2018) Molecular mechanisms for herpes simplex virus type 1 pathogenesis in Alzheimer’s disease. Front Aging Neurosci 10, 48.

146.

Shipley

, Parkin

, Itzhaki

, Dobson

(2005) Herpes simplex virus interferes with amyloid precursor protein processing. BMC Microbiol 5, 48.

147.

Little

, Joyce

, Hammond

, Matta

, Cahn

, Appelt

, Balin

(2014) Detection of bacterial antigens and Alzheimer’s disease-like pathology in the central nervous system of BALB/c mice following intranasal infection with a laboratory isolate of Chlamydia pneumoniae. Front Aging Neurosci 6, 304.

148.

Kumar

, Choi

, Washicosky

, Eimer

, Tucker

, Ghofrani

, Lefkowitz

, McColl

, Goldstein

, Tanzi

, Moir

(2016) Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 8, 340ra372.

149.

Tanaka

, Nagashima

(2018) Establishment of an Alzheimer’s disease model with latent herpesvirus infection using PS2 and Tg2576 double transgenic mice. Exp Anim 67, 185–192.

150.

Robinson

, Bishop

(2002) Abeta as a bioflocculant: Implications for the amyloid hypothesis of Alzheimer’s disease. Neurobiol Aging 23, 1051–1072.

151.

Eimer

, Vijaya Kumar

, Navalpur Shanmugam

, Rodriguez

, Mitchell

, Washicosky

, Gyorgy

, Breakefield

, Tanzi

, Moir

(2018) Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 100, 1527–1532.

152.

Bourgade

, Garneau

, Giroux

, Le Page

, Bocti

, Dupuis

, Frost

, Fulop

Jr (2015) β-amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16, 85–98.

153.

Itzhaki

(2018) Corroboration of a major role for herpes simplex virus type 1 in Alzheimer’s disease. Front Aging Neurosci 10, 324.

154.

Itzhaki

(2017) Herpes simplex virus type 1 and Alzheimer’s disease: Possible mechanisms and signposts. FASEB J 31, 3216–3226.

155.

Grimaldi

, Zappala

, Iemolo

, Castellano

, Ruggieri

, Bruno

, Paolillo

(2014) A pilot study on the use of interferon beta-1a in early Alzheimer’s disease subjects. J Neuroinflammation 11, 30.

156.

Lam

, Mapletoft

, Miller

(2016) Abnormal regulation of the antiviral response in neurological/neurodegenerative diseases. Cytokine 88, 251–258.

157.

Carr

, Al-khatib

, James

, Silverman

(2003) Interferon-beta suppresses herpes simplex virus type 1 replication in trigeminal ganglion cells through an RNase L-dependent pathway. J Neuroimmunol 141, 40–46.

158.

Sainz

Jr. , Halford

(2002) Alpha/Beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1. J Virol 76, 11541–11550.

159.

Pierce

, DeSalvo

, Foster

, Kosinski

, Weller

, Halford

(2005) Beta interferon and gamma interferon synergize to block viral DNA and virion synthesis in herpes simplex virus-infected cells. J Gen Virol 86, 2421–2432.

160.

Peng

, Zhu

, Hwangbo

, Corey

, Bumgarner

(2008) Independent and cooperative antiviral actions of beta interferon and gamma interferon against herpes simplex virus replication in primary human fibroblasts. J Virol 82, 1934–1945.

161.

Costa

, Agostini

, Guerini

, Mancuso

, Zanzottera

, Ripamonti

, Racca

, Nemni

, Clerici

(2017) Modulation of immune responses to herpes simplex virus type 1 by IFNL3 and IRF7 polymorphisms: A study in Alzheimer’s disease. J Alzheimers Dis 60, 1055–1063.

162.

Aurelius

, Andersson

, Forsgren

, Skoldenberg

, Strannegard

(1994) Cytokines and other markers of intrathecal immune response in patients with herpes simplex encephalitis. J Infect Dis 170, 678–681.

163.

Cheon

, Bajo

, Gulesserian

, Cairns

, Lubec

(2001) Evidence for the relation of herpes simplex virus type 1 to Down syndrome and Alzheimer’s disease. Electrophoresis 22, 445–448.

164.

Shimeld

, Whiteland

, Nicholls

, Grinfeld

, Easty

, Gao

, Hill

(1995) Immune cell infiltration and persistence in the mouse trigeminal ganglion after infection of the cornea with herpes simplex virus type 1. J Neuroimmunol 61, 7–16.

165.

Shimeld

, Whiteland

, Williams

, Easty

, Hill

(1997) Cytokine production in the nervous system of mice during acute and latent infection with herpes simplex virus type 1. J Gen Virol 78 (Pt 12), 3317–3325.

166.

Sun

, Wu

, Du

, Chen

(2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791.

167.

, Wu

, Gao

, Wang

, Sun

, Chen

(2013) Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390–1394.

168.

Zhang

, Zhao

, Xu

, Li

, He

, Zeng

, Xie

, Liu

, Lee

, Seo

, Chen

, Stabell

, Xia

, Sawyer

, Jung

, Huang

, Feng

(2018) Species-specific deamidation of cGAS by herpes simplex virus UL37 protein facilitates viral replication. Cell Host Microbe 24, 234–248.e235.

169.

Dong

, Feng

, Sun

, Li

, Wu

, Sun

, Tibbetts

, Chen

, Feng

(2010) Murine gamma-herpesvirus 68 hijacks MAVS and IKKbeta to initiate lytic replication. PLoS Pathog 6, e1001001.

170.

Dong

, He

, Durakoglugil

, Arneson

, Shen

, Feng

(2012) Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation. J Virol 86, 1930–1941.

171.

, Zhao

, Song

, He

, Minassian

, Zhou

, Zhang

, Brulois

, Wang

, Cabo

, Zandi

, Liang

, Jung

, Zhang

, Feng

(2015) Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production. Mol Cell 58, 134–146.

172.

Zhao

, Li

, Xu

, Feng

(2016) Emerging roles of protein deamidation in innate immune signaling. J Virol 90, 4262–4268.

173.

Zhao

, Zeng

, Xu

, Chen

, Shen

, Yu

, Knipe

, Yuan

, Peng

, Xu

, Zhang

, Xia

, Feng

(2016) A viral deamidase targets the helicase domain of RIG-I to block RNA-induced activation. Cell Host Microbe 20, 770–784.

174.

Seth

, Sun

, Ea

, Chen

(2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682.

175.

, Wang

, Han

, Li

, Zhai

, Shu

(2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19, 727–740.

176.

Meylan

, Curran

, Hofmann

, Moradpour

, Binder

, Bartenschlager

, Tschopp

(2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172.

177.

Strandberg

, Pitkala

, Linnavuori

, Tilvis

(2004) Cognitive impairment and infectious burden in the elderly. Arch Gerontol Geriatr Suppl 419–423.

178.

Elkind

, Ramakrishnan

, Moon

, Boden-Albala

, Liu

, Spitalnik

, Rundek

, Sacco

, Paik

(2010) Infectious burden and risk of stroke: The northern Manhattan study. Arch Neurol 67, 33–38.

179.

Rupprecht

, Blankenberg

, Bickel

, Rippin

, Hafner

, Prellwitz

, Schlumberger

, Meyer

(2001) Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease. Circulation 104, 25–31.

180.

Katan

, Moon

, Paik

, Sacco

, Wright

, Elkind

(2013) Infectious burden and cognitive function: The Northern Manhattan Study. Neurology 80, 1209–1215.

181.

Wozniak

, Itzhaki

, Shipley

, Dobson

(2007) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett 429, 95–100.

182.

Soscia

, Kirby

, Washicosky

, Tucker

, Ingelsson

, Hyman

, Burton

, Goldstein

, Duong

, Tanzi

, Moir

(2010) The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 5, e9505.

183.

Strandberg

, Pitkala

, Linnavuori

, Tilvis

(2003) Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke 34, 2126–2131.

184.

, Yao

, Jiao

, Zeng

, Liu

, Xiang

, Liang

, Wang

, Cao

, Yi

, Deng

, Liu

, Xu

, Zhang

, Gao

, Xu

, Zhang

, Wang

, Tan

, Xu

, Zhou

, Wang

(2015) A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol 22, 1519–1525.

185.

Barnes

, Capuano

, Aiello

, Turner

, Yolken

, Torrey

, Bennett

(2015) Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J Infect Dis 211, 230–237.

186.

Liu

, Giunta

, Zhou

, Tan

, Wang

(2012) Immunotherapy for Alzheimer disease: The challenge of adverse effects. Nat Rev Neurol 8, 465–469.

187.

Carter

(2011) Alzheimer’s disease: APP, gamma secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and their relationships with herpes simplex, C. pneumoniae, other suspect pathogens, and the immune system. Int J Alzheimers Dis 2011, 501862.

188.

Wright

, Gardener

, Dong

, Yoshita

, DeCarli

, Sacco

, Stern

, Elkind

(2015) Infectious burden and cognitive decline in the Northern Manhattan Study. J Am Geriatr Soc 63, 1540–1545.

189.

Readhead

, Haure-Mirande

, Funk

, Richards

, Shannon

, Haroutunian

, Sano

, Liang

, Beckmann

, Price

, Reiman

, Schadt

, Ehrlich

, Gandy

, Dudley

(2018) Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99, 64–82.e67.

190.

Itzhaki

, Lin

, Shang

, Wilcock

, Faragher

, Jamieson

(1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241–244.

191.

Itzhaki

, Lin

(1998) Herpes simplex virus type I in brain and the type 4 allele of the apolipoprotein E gene are a combined risk factor for Alzheimer’s disease. Biochem Soc Trans 26, 273–277.

192.

Linard

, Letenneur

, Garrigue

, Doize

, Dartigues

, Helmer

(2020) Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer’s disease. Alzheimers Dement 16, 200–208.

193.

Jayasuriya

, Itzhaki

, Wozniak

, Patel

, Smit

, Noone

, Gilleran

, Taylor

, White

(2008) Apolipoprotein E-epsilon 4 and recurrent genital herpes in individuals co-infected with herpes simplex virus type 2 and HIV. Sex Transm Infect 84, 516–517.

194.

Kuhlmann

, Minihane

, Huebbe

, Nebel

, Rimbach

, disease (2010) Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: A literature review. Lipids Health Dis 9, 8.

195.

Huemer

, Menzel

, Potratz

, Brake

, Falke

, Utermann

, Dierich

(1988) Herpes simplex virus binds to human serum lipoprotein. Intervirology 29, 68–76.

196.

, Pitas

, Mahley

(1998) Differential cellular accumulation/retention of apolipoprotein E mediated by cell surface heparan sulfate proteoglycans. Apolipoproteins E3 and E2 greater than e4. J Biol Chem 273, 13452–13460.

197.

Appleby

, Nacopoulos

, Milano

, Zhong

, Cummings

(2013) A review: Treatment of Alzheimer’s disease discovered in repurposed agents. Dement Geriatr Cogn Disord 35, 1–22.

198.

Burgos

, Ramirez

, Sastre

, Bullido

, Valdivieso

(2003) ApoE4 is more efficient than E3 in brain access by herpes simplex virus type 1. Neuroreport 14, 1825–1827.

199.

Koelle

, Magaret

, Warren

, Schellenberg

, Wald

(2010) APOE genotype is associated with oral herpetic lesions but not genital or oral herpes simplex virus shedding. Sex Transm Infect 86, 202–206.

200.

Lin

, Shang

, Wilcock

, Itzhaki

(1995) Alzheimer’s disease, herpes simplex virus type 1, cold sores and apolipoprotein E4. Biochem Soc Trans 23, 594s.

201.

Lovheim

, Norman

, Weidung

, Olsson

, Josefsson

, Adolfsson

, Nyberg

, Elgh

(2019) Herpes simplex virus, APOEvarepsilon4, and cognitive decline in old age: Results from the Betula Cohort Study. J Alzheimers Dis 67, 211–220.

202.

Strandberg

, Pitkala

, Eerola

, Tilvis

, Tienari

(2005) Interaction of herpesviridae, APOE gene, and education in cognitive impairment. Neurobiol Aging 26, 1001–1004.

203.

Itzhaki

, Wozniak

, Appelt

, Balin

(2004) Infiltration of the brain by pathogens causes Alzheimer’s disease. Neurobiol Aging 25, 619–627.

204.

Carter

(2010) APP, APOE, complement receptor 1, clusterin and PICALM and their involvement in the herpes simplex life cycle. Neurosci Lett 483, 96–100.

205.

Kristen

, Sastre

, Munoz-Galdeano

, Recuero

, Aldudo

, Bullido

(2018) The lysosome system is severely impaired in a cellular model of neurodegeneration induced by HSV-1 and oxidative stress. Neurobiol Aging 68, 5–17.

206.

Burgos

, Ramirez

, Sastre

, Bullido

, Valdivieso

(2002) Involvement of apolipoprotein E in the hematogenous route of herpes simplex virus type 1 to the central nervous system. J Virol 76, 12394–12398.

207.

Smith

, Sikes

, Levin

(1998) Human apolipoprotein E allele-specific brain expressing transgenic mice. Neurobiol Aging 19, 407–413.

208.

Itzhaki

, Wozniak

(2012) Could antivirals be used to treat Alzheimer’s disease? Future Microbiol 7, 307–309.

209.

Mardare

(1998) Asymptotic analysis of linearly elastic shells: Error estimates in the membrane case. Asymptotic Anal 17, 31–51.

210.

Burgos

, Ramirez

, Sastre

, Valdivieso

(2006) Effect of apolipoprotein E on the cerebral load of latent herpes simplex virus type 1 DNA. J Virol 80, 5383–5387.