A Review of the Familial Alzheimer’s Disease Locus PRESENILIN 2 and Its Relationship to PRESENILIN 1

Abstract

PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer’s disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis.

Keywords

Alzheimer’s disease γ-secretase PRESENILIN 1 PRESENILIN 2

INTRODUCTION

PRESENILINs are essential components of the γ-secretase complex and both the PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer’s disease (fAD) [1]. Interestingly, there have been nearly 200 potentially pathogenic mutations identified in PSEN1, but only 16 pathogenic mutations (Fig. 1 and Table 1) have been reported in PSEN2 to date [2, 3]. It appears that, although these two PRESENILIN proteins are highly homologous (they share 62% identity at the amino acid residue sequence level [4]), they can contribute to different biological processes [5, 6]. However, the complete function of the two PRESENILIN genes and how they contribute to fAD pathogenesis has not yet been determined. Due to the nearly 200 pathogenic mutations in PSEN1 this gene has been extensively covered in the literature, while PSEN2 has not received as much attention. This review provides a summary of the overlapping and independent functions of the PRESENILINs, with a focus on the physiological activities of PSEN2.

Fig. 1.

Mutations in PSEN2. Red: mutation is pathogenic; Orange: pathogenic nature is unclear or possible pathogenic; Green: mutation is not pathogenic. Adapted from http://www.molgen.vib-ua.be/ADMutations to include all mutations from Table 1 [3].

Table 1

fAD mutations in PSEN2

Mutation	Allele Frequency	Clinical Significance	AD Mean of Onset age (y)	Reference
1:227069661 C / T p.Thr18Met	2.473e-05	Pathogenic nature unclear with Parkinson’s disease	N/A	[137]
1:227069694 G / A p.Arg29His	2.482e-05	Not pathogenic	no AD diagnosis	[138]
1:227069708 G / A p.Gly34Ser	0.0004718	Pathogenic nature unclear	N/A	[139]
1:227071448 C / T p.Arg62Cys	0.0001653	Pathogenic nature unclear	76.5	[139 –141]
1:227071449 G /A p.Arg62His	0.009897	Pathogenic nature unclear with Frontotemporal Dementia	55.8	[140 , 142–144]
1:227071469 C / G p.Pro69Ala	9.078e-05	Possible Pathogenic	75	[145]
1:227071475 C / T p.Arg71Trp	0.003357	Possible Pathogenic	68.4	[139 , 146]
1:227071509 A / G p.Lys82Arg*	N/A	Possible Pathogenic	53	[147]
1:227071518 C / T p.Ala85Val	8.245e-06	Pathogenic with Parkinsonism	63.6	[148]
1:226883908 del G A p.Lys115fs*	N/A	Pathogenic	65	[2]
1:27073246 A / C p.Thr122Pro	0.000399361	Likely Pathogenic	47.9	[149, 150]
1:227073247 C / G p.Thr122Arg	0.00020	Pathogenic with Frontotemporal Dementia	57.3	[151]
1:227073250 C / T p.Pro123Leu*	N/A	Likely Pathogenic	57	[152]
1:227073258 G / A p.Glu126Lys	N/A	Likely Pathogenic With Parkinson’s disease	49	[153]
1:227073271 C / T p.Ser130Leu	0.0006438	Pathogenic nature unclear	70.6	[154, 155]
1:227073297 G / A p.Val139Met	0.0001079	Pathogenic nature unclear	76	[156]
1:227073303 A / T p.Asn141Tyr	N/A	Pathogenic	46	[157]
1:227073304 A / T p.Asn141Ile	N/A	Pathogenic	56.2	[7 , 158]
1:227073310 T / A p.Leu143His	N/A	Not pathogenic	no AD diagnosis	[138]
1:227073324 G / A p.Val148Ile	N/A	Pathogenic	71	[159]
1:227073364 A / G p.Lys161Arg	8.265e-06	Possible Pathogenic	N/A	[160]
1:227073370 G / A p.Arg163His	2.48e-05	Not pathogenic - Observed in a Parkinson’s disease patient with a SNCA mutation and unaffected mother	no AD diagnosis	[161]
1:227075798 C / A p.His169Asn*	0.0001648	Possible Pathogenic with Frontotemporal Dementia	68	[147]
1:227075813 A / G p.Met174Val	0.0006343	Pathogenic	55.3	[162]
1:227075817 C / G p.Ser175Cys	8.237e-06	Pathogenic	60.5	[163]
1:22707659? ? / ? p.Gly212Val*	N/A	Pathogenic	60–65	[164]
1:227076603 G / T p.Val214Leu	0.0001895	Possible Pathogenic	69	[147, 165]
1:227076646 A / T p.Gln228Leu	1.648e-05	Pathogenic	70	[166]
1:227076655 A / G p.Tyr231Cys	8.241e-06	Pathogenic with Frontotemporal Dementia	58.5	[167]
1:227076666 A / T p.Ile235Phe	N/A	Possible Pathogenic	N/A	[168]
1:227076673 C / T p.Ala237Val	5.775e-05	Pathogenic	87	[169]
1:227076675 C / T p.Leu238Phe	1.65e-05	Pathogenic	54	[137]
1:227076678 A / G p.Met239Val	N/A	Pathogenic	51.5	[158 , 170]
1:227076680 G / A p.Met239Ile	N/A	Pathogenic	50.7	[8, 149]
1:227076717 G / A p.Ala252Thr	0.0002512	Not pathogenic	no AD diagnosis	[138]
1:227079473 C / G p.Pro334Ala	8.238e-06	Not pathogenic	no AD diagnosis	[168]
1:227079474 C / G p.Pro334Arg	4.943e-05	Not pathogenic	no AD diagnosis	[171]
1:227079516 C / T p.Pro348Leu	N/A	Possible Pathogenic	65	[137]
1:227081765 C / T p.Ala377Val	5.796e-05	Not pathogenic	no AD diagnosis	[168]
1:227081812 G / A p.Val393Met	0.0001323	Likely Pathogenic	70	[172]
1:227083195 C / T p.Thr421Met	3.378e-05	Pathogenic nature unclear	55	[173]
1:227083222 C / T p.Thr430Met	3.481e-05	Pathogenic	56.3	[9, 174]
1:227083249 A / C p.Asp439Ala	3.764e-05	Possible Pathogenic	65.5	[174, 175]

Data adapted from PSEN2 mutations recorded in the Alzheimer Disease & Frontotemporal Dementia Mutation Database (AD/FTD database); http://www.molgen.ua.ac.be/ADMutations/default.cfm [3] except those indicated by “*”. Mutations are based on PSEN2 transcript NM_000447.2. ExAC Browser; http://exac.broadinstitute.org/ and ClinVar; https://www.ncbi.nlm.nih.gov/clinvar databases were searched to identify allele frequency information (if available) for each mutation/variant. Clinical significance information was inferred from the AD/FTD database (database terms used: pathogenic, pathogenic nature unclear and not pathogenic) and ExAc Browser (database terms used: pathogenic, possible pathogenic and likely pathogenic), see references for further detailed clinical information for each mutation. AD, Alzheimer’s disease, N/A (and “?”), not available.

FAMILIAL ALZHEIMER’S DISEASE MUTATIONS IN PSEN2

PSEN2 was first identified as STM2, a candidate gene for the chromosome 1 AD locus, when a point mutation resulting in the substitution of an isoleucine for an asparagine (N141I) was found in a Volga German AD family in 1995 [7]. The fAD mutations in PSEN2 are notable for a number of reasons. Unlike fAD mutations in PSEN1, PSEN2 variants demonstrate incomplete penetrance [2 , 9] with the mean [10] age at symptom onset of the fAD mutations in PSEN2 as a group being more than 10 years later than the mean for PSEN1 fAD mutations [10]. (The one exception is the PSEN2 N141I variant that shows nearly complete penetrance with few “escapees” beyond age 80). Variable expressivity and clinical overlap with late onset “sporadic” AD suggest it is possible that PSEN2 variants may be more common in the general AD population than previous early onset family studies have indicated.

All but one of the known fAD mutations in PSEN2 are similar to those in PSEN1 in that they follow the “fAD mutation reading frame preservation rule” [11]. The mutations permit production of transcripts encoding proteins that include C-terminal sequence. The apparent exception is the K115fs mutation that results from a two-nucleotide deletion near the downstream end of exon 4 [2]. This mutation is interesting in that it appears to mimic expression of a naturally truncated isoform of PSEN2 denoted PS2V ([12, 13], see later). However, in the presence of the two-nucleotide deletion of K115fs, the alternative splicing event that generates PS2V (by exclusion of exon 5 sequence) actually reinstates the original reading frame of the gene so that such transcripts may encode a mutant protein that includes the normal C-terminal sequence. Therefore, the K115fs mutation may be the exception that proves the “fAD mutation reading frame preservation rule”.

PSEN2 PROTEIN AND THE γ-SECRETASE COMPLEX

Presenilins are the catalytic core of the γ-secretase complex that functions to cleave a number of type I membrane proteins. The other three structural subunits of the γ-secretase complex are nicastrin (NCT), PSEN enhancer 2 (PSENEN or PEN-2), and either anterior pharynx 1 (APH-1) a or b [14]. NCT functions as a γ-secretase substrate receptor [15]. PSENEN is required for the stabilization of the heterodimer of PRESENILIN N- and C-terminal fragments within the γ-secretase complex [16]. APH-1 stabilizes newly synthesized PRESENILIN holoprotein, and is possibly able to downregulate the activity of uncleaved PRESENILIN holoprotein that antagonizes cell proliferation (or promotes cell death) [17].

The PSEN2 protein is a 50 to 55kDa protein consisting of nine transmembrane domains (TMDs), a cytosolic N-terminus, a lumenal C-terminus and a “cytosolic loop” between the sixth and seventh TMD [2]. The active site of the γ-secretase complex is thought to be formed by two aspartyl residues in adjacent TMDs, residues D263 and D366 of PSEN2 (residues D257 and D385 in PSEN1) [18, 19]. PSEN2 can be cleaved by γ-secretase itself, within the cytosolic loop, to generate a longer N-terminal fragment (NTF) and a shorter C-terminal fragment (CTF) [20, 21]. Two well-studied substrates of γ-secretase are the amyloid precursor protein (AβPP) and Notch. A cytosolic CTF is normally generated by the cleavage of these transmembrane proteins by γ-secretase. For Notch, this fragment is identified as Notch intracellular domain (NICD) [22]. The CTF produced by γ-secretase is then translocated to the nucleus to modulate gene expression [23].

A well-studied substrate of the γ-secretase complex is AβPP, a type I membrane protein that can be cleaved through either non-amyloidogenic or amyloidogenic pathways (Fig. 2). The non-amyloidogenic pathway is more prevalent in most cell types [24]. In this pathway, AβPP is first cleaved by α-secretase into a soluble N-terminal fragment (sAβPPα) and an 83 amino acid C-terminal fragment (named as α-CTF or C83). The C83 fragment is then cleaved by γ-secretase into an AβPP intracellular domain (AICD) and a p3 peptide. The amyloidogenic pathway is an important processing pathway in neurons. In this pathway, AβPP is first cleaved by β-secretase into sAβPPβ and β-CTF (also named C99). The C99 fragment is then cleaved by γ-secretase into AICD and Aβ [25]. Cleavage at three major sites in AβPP is mediated by γ-secretase (Fig. 2), namely cleavage at the ɛ-site to produce a 49 amino acid residue (aa) form of Aβ (Aβ₄₉), ζ-site cleavage (Aβ₄₆) and γ-site cleavage (Aβ₄₂_/40) [26, 27].

Fig. 2.

Processing of AβPP through either the non-amyloidogenic or amyloidogenic pathways.

Aβ₄₀ (the 40aa form of Aβ) is the predominant Aβ species produced, while Aβ₄₂ is a minor product of AβPP cleavage. Aβ₄₀ and Aβ₄₂ are produced from two different “production lines” of sequential cleavage by the γ-secretase enzyme, Aβ₄₉ >Aβ₄₆ >Aβ₄₃ >Aβ₄₀ and Aβ₄₈ >Aβ₄₅ >Aβ₄₂ >Aβ₃₈. In these production lines, long Aβs are shortened by consecutive carboxypeptidase-like γ-cleavages, and the hydrophobicity of Aβs can be decreased during this process, so that these Aβs are more easily moved into the extracellular environment [28]. Aβ₄₂ has a much stronger tendency to aggregate than Aβ₄₀ [29], as the biophysical and biochemical properties of Aβ vary strongly with its length [30, 31]. Normally, Aβ₄₂ only constitutes about 10% of total secreted Aβ [32]. However, since longer Aβ peptides promote aggregation and neurotoxicity, an increase in the relative amount of Aβ₄₂ versus Aβ₄₀, (caused either by an increase in Aβ₄₂ production or by a decrease in Aβ₄₀ levels), has been proposed to be involved in the pathogenesis of AD [33]. Some of the fAD mutations in PSEN2 (and PSEN1) have been reported to cause increased ratios of Aβ₄₂/₄₀ [27 , 34–36].

The contribution of PSEN1 and PSEN2 to γ-secretase activity has been studied and quantified in various systems. The loss of PSEN1 is thought to reduce the activity of γ-secretase complexes [37, 38], and the loss of both PSEN1 and PSEN2 is thought to eliminate the γ-secretase activity of such complexes completely [39, 40]. Although these two PRESENILINs are thought to complement each other functionally, they also have distinct individual functions. Psen1 is thought to contribute more to γ-secretase-associated AβPP and Notch cleavage than Psen2 since knockout of Psen1 in mice resulted in an embryonic lethal phenotype and a significant decrease in Aβ levels [41, 42], while knockout of Psen2 resulted in no overt embryonic phenotype or change of Aβ levels [43]. In mouse blastocyst-derived (BD) cells that were transiently transfected with the C100 fragment of APP (C99 with an additional translation start codon), the relative cellular activity of Psen1-associated-γ-secretase complexes (in Psen1 ^+/–Psen2^–/– BD cells) was found to be ∼38-fold greater than that of Psen2-associated-γ-secretase complexes (in Psen1^–/–Psen2 ^+/+ BD cells), indicating that Psen1 may be more active than Psen2 toward AβPP’s C100 fragment [5]. The activities of Psen1-associated γ-secretase complexes and Psen2-associated γ-secretase complexes could be discriminated based on their susceptibility to potent γ-secretase inhibitors, therefore these two classes of γ-secretase complexes probably have different active sites with different substrate preferences. This study also revealed that only ∼14% of the Psen1 in wild-type BD cells was engaged in active γ-secretase complexes, suggesting that the remaining Psen1 serves other biological functions [5]. Expression of human PSEN1 in Psen1^–/–Psen2^–/– mouse fibroblasts, could generate more Aβ (resulting from γ-site cleavage) than expressing human PSEN2, while the levels of the physiologically active AβPP intracellular domain (AICD) product (resulting from ɛ-site cleavage) provided by these two PRESENILINs were the same [44]. In a yeast reconstitution system, it has been found that PSEN1-associated-γ-secretase complexes can generate ∼24-fold more total Aβ than PSEN2-associated-γ-secretase complexes (measured by secreted Aβ per γ-secretase complex). However, the amount of PSEN1 in the γ-secretase complexes was ∼28 times higher than that of PSEN2, suggesting that PSEN1 does not have higher activity than PSEN2 in Aβ production [45].

Interestingly, one hypothesis suggests that, since PSEN2 generates less Aβ than PSEN1, mutations in PSEN2 that cause AD must result in a more severe impact on γ-secretase than those in PSEN1, so that the effect on Aβ levels can be strong enough to produce the disease in the presence of normal PSEN1 alleles [46]. Functional analyses of putative PSEN2 fAD mutations also supported this hypothesis, as these mutations cause dramatic changes in the Aβ_42/40 ratio [46] and this ratio is proposed to be related to development of AD [47, 48]. Furthermore, these analyses revealed that most of the PSEN2 mutations also show parallel decreases in the generation of CTFγ, a CTF generated from the cleavage of AβPP by γ-secretase, as well as decreased Notch intracellular domain (NICD) production. Some very early-onset PSEN1 fAD mutations also show similar effects on CTFγ and NICD production [46].

THE ROLE OF PSEN2 IN INNATE IMMUNITY VIA γ-SECRETASE ACTIVITY

Dysfunction of the immune system has been considered a major factor in AD [49]. As one of the important immune cell types, microglia are essential for surveillance, and rapidly respond to changes in the central nervous system (CNS) [50]. However, in some neurodegenerative diseases, microglia may also cause neuronal injury through upregulating production of inflammatory cytokines, neurotoxins, excitotoxins, and reactive oxygen species [51, 52]. In AD, microglia are able to bind to Aβ through cell-surface receptors and drive Aβ fibrils into the endolysosomal pathway [53]. Thus, microglia are key components for Aβ clearance.

Psen2 may play a specific role in CNS innate immunity not performed by Psen1. In a mouse microglial cell line, Psen1 and Psen2 show compensatory regulation (i.e., knockdown of one leads to upregulation of the other); however, only Psen2 knockdown results in markedly decreased γ-secretase activity that leads to an exaggerated proinflammatory cytokine release from microglia [51]. miR146, a negative regulator of monocyte pro-inflammatory response, is constitutively down-regulated in microglia isolated from Psen2 knockout mice [54]. While reduced responsiveness to lipopolysaccharide (LPS) and reduced pro-inflammatory cytokine production together with decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activity has been reported in Psen2- (but not Psen1-) knockout mice [55]. These studies suggest that Psen2 may be the predominant γ-secretase in microglia and that deficiency of only Psen2 function (not Psen1) is associated with exaggerated microglial pro-inflammatory responses.

PSEN2 AND NEURAL DEVELOPMENT

In mice, the absence of both Psen1 and Psen2 genes simultaneously results in embryonic lethality, indicating that Presenilins are essential for embryonic development [41, 56]. The embryos of Psen1 and Psen2 double knockout mice display a loss of neural progenitor cells (NPCs) and disrupted neuronal migration at embryonic day 11 [57]. The Notch signaling pathway, which controls cellular fate choices throughout neurodevelopment [58], was also found to be blocked in double knockout mouse embryos, indicating that Presenilins are essential for neural development [57, 59]. Premature differentiation of NPCs and inhibition of the Notch signaling pathway (as well as skeletal defects [42]) were also observed in Psen1 knockout mice and resulted in perinatal lethality [41, 60]. In comparison, Psen2 knockout mice are viable and fertile [43] and do not show any effect on the physiologically important process of apoptosis during embryonic development [61]. This indicates that, in mice, only Psen1 is essential for neural development, in contrast to Psen2 [43].

THE ROLE OF γ-SECRETASE IN TUMORIGENESIS

An inverse association between cancer and AD has been observed in a population-based cohort study, which revealed that patients with prevalent cancer had a 43% lower risk of developing AD, while those with AD had a 69% lower risk of having cancer [62]. Unsurprisingly, there are several lines of evidence linking Presenilins and γ-secretase activity to tumorigenesis.

Presenilins are thought to have an anti-oncogenic function since the overexpression of both Presenilin genes promotes cellular apoptosis [63, 64], and the knockout of either Presenilin gene results in higher rates of tumorigenesis [65 –67]. The AICD produced through γ-secretase cleavage of AβPP was found to be able to regulate epidermal growth factor receptor (EGFR) transcription (which is upregulated in a wide variety of tumors) via binding to the EGFR promoter to provide a tumor suppressive effect [68]. Overexpression of both wild type and mutant PSEN2 (N141I) in cultured neural cells (PC12 cells) was found to induce apoptosis in the absence of an apoptotic insult [69, 70], while no spontaneous apoptosis was observed in PC12 cells with overexpression of either wild type or fAD mutant PSEN1 (either the L286V or M146V mutation) [71]. Furthermore, the anti-apoptotic oncogene bcl-2 was found to be downregulated during PSEN2-mediated apoptosis in primary cultured neurons [72]. A recent study by Park et al. demonstrated decreased expression of Peroxiredoxin 6 (PRDX6) (a tumor-promoting protein), in AD patients with mutation of PSEN2 [73]. Further analysis of a mutant PSEN2 (N141I) mouse model verified that reduced PRDX6 activity occurred due to an increased γ-secretase activity and this resulted in a reduced incidence of spontaneous and carcinogen-induced lung tumor development [73].

DOES PSEN2 HAVE A ROLE IN AUTOPHAGY?

Autophagic/lysosomal dysfunction is thought to be extensively involved in the neurodegenerative process in AD since the endosomal-lysosomal system is a prominent site of AβPP processing, Aβ uptake, and Aβ production [74]. The transport of autophagic vacuoles (AVs) and their maturation to lysosomes may be impaired in AD brains [75], and significant accumulations of AVs have also been detected in AD brains [76].

Lee et al. [77] showed that deletion of the Psen1 gene in murine blastocysts caused complete loss of macroautophagy without affecting non-lysosomal forms of proteolysis. This was due to the failure of the V0a1 subunit of v-ATPase to become N-glycosylated in the endoplasmic reticulum (ER), resulting in a selective impairment of autolysosome acidification and cathepsin activation [77]. While there is data showing involvement of PSEN2 in autophagy (see below) its role in lysosomal acidification has not yet been tested.

In human fibroblasts, fAD mutations in PSEN1 resulted in even more severe impairment of lysosomal/autophagic functions compared to the affects seen in PSEN1 knockout cells [77]. This effect was independent of γ-secretase activity since chemical inhibition or the absence of Nicastrin (an essential component of the γ-secretase complex) did not affect autophagy [77]. However, the roles of PRESENILINs in lysosomal/autophagic functions are still controversial. Another study by Neely et al. [78] revealed that, although the deletion of either Psen1 or Psen2 in mouse embryonic fibroblasts caused impaired autophagic function, no deficits in lysosomal acidification were found [78]. In that study, it was also found that deletion of both Presenilins in mouse fibroblasts (which resulted in loss of γ-secretase activity) led to impaired autophagic function. As previously demonstrated by Lee et al., the 2011 Neely et al. study also showed that γ-secretase inhibitors did not adversely impact autophagy [77], indicating that Presenilins are involved in the autophagic function in a γ-secretase-independent manner [78]. It was also revealed that, although both Presenilins are involved in regulating autophagy, one cannot compensate for the loss of the other [78], suggesting separate independent functions for the Presenilins in autophagy. Additionally, in PSEN1^–/– hippocampal neurons, a greatly decreased lysosomal calcium release that altered ion channels in the endoplasmic reticulum has been reported [79]. Similar alterations in calcium homeostasis and reduced autophagic function were also observed in Presenilin-double knockout mouse embryonic fibroblasts, which supports that Presenilins are necessary for calcium homeostasis [80].

In a major paper in 2016, Sannerud et al. [81] demonstrated that an evolutionarily conserved, unique acidic-dileucine sorting motif near the N-terminal of PSEN2 interacts with the trans-Golgi network (TGN)/endosomal adaptor complex protein (AP) complex AP-1 in a manner modulated by phosphorylation. This directs PSEN2 protein specifically into the late endosome/lysosome system compared to PSEN1’s broader subcellular distribution. Interestingly, these researchers also saw that a number of fAD mutations in PSEN1 caused the distribution of PSEN1 protein to resemble more closely that of PSEN2. Melanophores are organelles containing the pigment melanin that are related to lysosomes (reviewed by [82]). Sannerud et al. saw that knockdown of PSEN2 expression in a human melanocyte cell line greatly affected γ-secretase cleavage of Tyrosinase-related protein 1 (TYRP1) and silver, mouse, homolog of (SILV) (also known as PMEL, PREMELANOSOME PROTEIN) that are both involved in melanosome biogenesis. The specific importance of PSEN2 for melanosome biogenesis is supported by our discovery that loss of psen2 gene function in zebrafish causes loss of surface melanotic pigmentation in adult fish [83].

PSEN2 AND CALCIUM HOMEOSTASIS

Calcium homeostasis has been found to play an important role in AD progression, and calcium dysregulation may contribute to increased Aβ production [84], enhanced vulnerability of neurons to apoptosis [85], and numerous processes underlying aging-related changes in the brain [86]. Moreover, changes in the concentration of calcium ions not only affect membrane channels but also diverse intracellular calcium-regulating structures and systems, such as mitochondria, and enzymes such as calcium-dependent ATPases [87].

Independent of their role in γ-secretase activity, PRESENILINs also appear to function as passive Ca^{2 +} leak channels in the ER [88]. Mutations in both PSEN1 and PSEN2 have been found to affect intracellular calcium homeostasis [89, 90]. Overexpression of fAD PSEN1 mutations in cultured neural cells resulted in increased cytoplasmic calcium and induced calcium release from the ER when stimulated by agonists (such as carbachol and bradykinin) [91]. It was reported that such elevations of calcium can induce oxidative stress [92, 93], which mediates staurosporine-induced mitochondrial dysfunction and apoptosis [94]. Mice with a knock-in of the fAD PSEN1 mutation, M146V, show elevation of cytoplasmic calcium levels in synaptosomes, but this was not seen in M146L knockin mice (possessing a different point mutation at the same amino acid position) that express lower and closer-to-physiological levels of mutant PSEN1 [95]. Mitochondrial dysfunction and caspase activation were also observed in synaptosomes of M146V knockin mice [95, 96].

The level of calcium in the ER is also dependent on plasma membrane store-operated calcium channels (SOCCs) during capacitative calcium entry (CCE) (also known as store-operated calcium entry) which is triggered by depletion of intracellular calcium stores) [97]. In PSEN1M146V knockin mouse fibroblasts, elevated ER calcium levels and deficits in CCE (but functional SOCCs) were detected [98]. Additionally, in CHO cells that stably overexpress wild type AβPP, both overexpression of the PSEN1 mutation, D257A, and co-expression of D257A and the PSEN2 mutation, D366A (mutations that decrease γ-secretase activity) resulted in reduced intracellular calcium stores and enhanced CCE compared to overexpression of wild type PSEN1. However, expression of another dominant negative isoform of PSEN1, ΔTM1-2 (which also abrogates γ-secretase activity), led to reduced intracellular calcium stores but with a deficit of CCE [99]. Thus, modulation of CCE appears to be independent of the function of PRESENILINs in γ-secretase activity [99].

The knockdown of the gene PSENEN in Hela cells results in inhibition of proteolytic processing of PRESENILINs [100], thus, increasing the holoprotein form of these proteins. The holoprotein form of Psen1 in Aph-1abc^–/– mouse embryonic fibroblasts (where γ-secretase activity is completely absent and Psen1 is present as a holoprotein) was found to increase greatly the calcium leak rate, strongly suggesting that the holoprotein forms of the Presenilins are the functional forms in calcium leakage [88].

Knockdown of PSEN2 activity in Hela cells was found to reduce dramatically the ER calcium leak rate and to produce a large increase in ER calcium load [100]. The PSEN2 fAD mutation, N141I, was found to induce ER calcium leak and reduce the ER calcium pool [88, 101]. However, in SH-SY5Y neuroblastoma cell lines, PSEN2, but not PSEN1, modulates the shuttling of Ca^{2 +} between the ER and mitochondria since mitochondrial Ca^{2 +} dynamics were reduced by PSEN2 down-regulation and enhanced by the expression of the PSEN2 mutant forms, N141I, D366A and T122R [102]. This specific function for PSEN2 in Calcium transport reinforces that the PRESENILINs have separate independent functions.

PRESENILINS ARE IMPORTANT FOR MITOCHONDRIAL FUNCTION

Mitochondria are essential for cellular energy supply and for other cellular processes such as apoptosis, reactive oxygen species production and calcium homeostasis [103]. The limited glycolytic capacity of neurons means that their energy supply is highly dependent on aerobic oxidative phosphorylation (OXPHOS) that occurs in mitochondria [104]. The “mitochondrial cascade hypothesis” postulates that mitochondrial dysfunction is a primary event in both sporadic and familial forms of AD [105, 106]. Although mutations in both PSEN1 and PSEN2 have been shown to sensitize cells to apoptosis through impaired mitochondrial function, there is evidence suggesting that PSEN2-associated γ-secretase activity may play a specific role required for proper mitochondrial function [63]. Overexpression of the PSEN2 fAD mutation, N141I, has been shown to induce apoptosis in PC12 cells [70] and to increase γ-secretase activity in mouse brain mitochondria [63]. This induced the production of Aβ₄₂ peptides and contributed to mitochondrial dysfunction and AD pathology [63]. In mouse embryonic fibroblasts (MEFs), it has been found that knockout of Psen2 caused a significantly lower basal respiratory rate compared to knockout of Psen1 or compared to wild type cells, and the percentage of fully functional mitochondria in Psen2 knockout cells (and Presenilin double knockout cells) was much lower than that in wild type cells or cells lacking only Psen1 [107]. A separate MEF study showed that a deficiency of Psen2 led to a reduction in the subunits responsible for mitochondrial OXPHOS, an altered morphology of the mitochondrial cristae and an increase in glycolytic flux. This indicated that absence of Psen2 causes an impairment in respiratory capacity but also an increase in glycolytic flux to support energy needs [108].

PSEN2 IS ENRICHED IN MITOCHONDRIA-ASSOCIATED ER MEMBRANES

Mitochondria-associated ER membranes (MAM) are a sub-compartment of the ER juxtaposed to mitochondria [109]. This compartment is involved in various cellular activities, such as calcium homeostasis [109, 110], cholesterol metabolism [111], and apoptosis [112]. These functions of MAM are also related to those dysregulated in AD [113]. Upregulation of MAM-associated proteins in both AD brain and an AβPP mouse model, increased ER-mitochondrial coupling in human fibroblasts from both fAD and sporadic AD patients [114]. The enrichment of PSEN1 and PSEN2 in the MAM [115] strongly supports a role for MAM in AD pathology.

A study by Pera et al. [116] focused on the accumulation of the AβPP C-terminal fragment, C99, in the MAM (this fragment becomes a substrate for the γ-secretase complex in the amyloidogenic pathway of AβPP cleavage). In cells from AD patients, and in the embryonic cortical neurons of a PSEN1 fAD mutation (M146V) knockin mouse, the level of unprocessed C99 was increased in MAM, which then induced sphingolipid turnover and ultimately resulted in the dysfunction of mitochondria [116].

In mice, Psen2 has been shown to bind to Mitofusin 2 (Mfn2), one of the major regulators of ER-mitochondria [117] and to induce ER-mitochondrial coupling [118]. Although Psen2 is not necessary for the antagonistic effect of Mfn2 on MAM formation (Mfn2 can antagonize ER-mitochondrial coupling in the absence of Psen2), the presence of Psen2 modulates the effect of Mfn2. Surprisingly, an fAD mutant form of PSEN2 (N141I) was shown to be more effective than the wild-type form in regulating ER-mitochondrial coupling, as its binding to Mfn2 is favored [118]. Although PSEN1 has been suggested to play a similar role in regulating ER-mitochondrial coupling to PSEN2 [119], it showed no interaction with Mfn2 (nor with its homologue Mfn1) [118].

PSEN2 AND ISCHEMIC OXIDATIVE STRESS

Brain ischemia has long been considered one of the possible causes of AD [120]. Dysregulated AβPP, the PRESENILINs, β-secretase and Apolipoproteins (the APOE ɛ4 allele is considered to be the major genetic risk locus for late onset, sporadic AD [121]) have been observed in experimental models of incomplete brain ischemia [122]. In rats, after 10 min of global brain ischemia, the expression of Psen1 showed a modest trend of downregulation from days 2 to 7 post-ischemia, with an opposite trend at day 30. The expression of Psen2 showed significant upregulation on day 2 post-ischemia and was only modestly elevated on day 7 followed by a slight downregulation on day 30, indicating that the two Presenilins may have different roles during brain ischemia in rats [123]. This brain ischemia model supported that PSEN2 plays a role in the modulation of apoptosis [72], since neurons in ischemic injured areas of the brain began to die from days 2 to 7 post-ischemia [123]. Although the PRESENILINs appear to complement each other’s functions, PSEN1 seems to provide a basic constitutive function, while PSEN2 appears to operate as an emergency aid under ischemic oxidative stress [124].

PS2V is a truncated isoform of the PSEN2 protein that shows enhanced expression in AD brains [12]. PS2V is produced by alternative transcript splicing that excludes exon 5 sequence from PSEN2 mRNA (Fig. 3) [12]. It was demonstrated in human neuroblastoma SK-N-SH cells, that the expression of PS2V is induced by hypoxia, but not by many other stresses [125]. This was also supported by observations in the guinea pig [126] and zebrafish [13]. However, the PS2V isoform appears to be absent in mice and rats [13]. In zebrafish, the PS2V-equivalent isoform, PS1IV, is produced when hypoxia induces alternative splicing of transcripts of the psen1 gene rather than transcripts of psen2. Although PS1IV is far smaller than PS2V, it is functionally similar to PS2V in that it is able to stimulate γ-secretase activity and suppress the unfolded protein response [13]. Further study of PS1IV revealed that its absence under hypoxia-like conditions changes the expression of genes involved in inflammation such as the gene il1b, which is equivalent to IL1B in humans, that is recognized as an AD risk locus [127, 128].

Fig. 3.

The generation of PS2V. Under hypoxia, reactive oxygen species production by mitochondria increases and induces the expression of HMGA1a that binds to PSEN2 transcripts at the 3’ end of exon 5. This excludes binding by splicing factors and causes exon 4 to be spliced to exon 6. This causes a frameshift that results in early termination of the coding sequence, translation of which produces PS2V [13]. The position of the 2-ncuelotide deletion K115fs mutation is indicated.

DIFFERENTIAL EXPRESSION OF THE PRESENILINS WITH AGE AND SEX

AD is more prevalent in women than men [129]. AD histopathology [130] and AD-related cognitive decline [131] reported to be greater in women than in men. Although the mechanism of this gender difference in AD risk is still unclear, sex steroid hormones are thought to be a contributing factor. Indeed, sex steroid hormones are known to be involved in neural development [132].

The expression of PRESENILINs has been found to change with age and sex. Thakur and Gosh have published a number of studies investigating Presenilin expression in the cerebral cortex of mice [133 –135]. In aged mice, Psen1 is downregulated and Psen2 is upregulated in both sexes. However, in female mice, the expression level of Psen1 is relatively higher and the expression level of Psen2 is relatively lower compared to males of the same age [133]. Follow-up studies found that the expression of Psen1 is downregulated by gonadal hormones (17β-estradiol and testosterone) in female and male adult mice and upregulated in aged male mice only [134]. After gonadectomy in female and male adults there was a decrease in Psen2 expression but supplementation with gonadal steroids could upregulate the expression of Psen2 in both sexes [135]. A separate study found that there was no difference in the levels of PSEN1 (and APP) proteins in hypogonadal female mice, while male hypogonadal mice had increased levels of these proteins and this was confined to the hippocampal region [136]. Collectively, these results suggest a sex-dependent regulation of brain Presenilin expression during aging and that the regulation of the Presenilins by gonadal steroids may influence Presenilin associated brain functions.

CONCLUSION

PSEN2 is one of the genes implicated in fAD pathogenesis, but our understanding of how it contributes to AD progression is still limited. As one of the essential components of the γ-secretase complex, PSEN2 protein has been found to be involved in γ-secretase-related physiological activities that are associated with AD progression such as innate immunity, Notch signaling, tumorigenesis and autophagy. PSEN2 also plays a specific role(s) in mitochondrial function due to its regulation of calcium homeostasis. Research using animal models has found that expression of Psen2 changes with age and sex, and, significantly, is altered under ischemic oxidative stress which is likely a major contributor to AD pathogenesis. However, this may be only the tip of the iceberg of PSEN2’s functions, and more research must be done to fully identify and understand PSEN2’s roles in normal cell biology and AD.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/18-0656r1).

References

Hutton

(1997) The presenilins and Alzheimer’s disease. Hum Mol Genet 6, 1639–1646.

Jayadev

, Leverenz

, Steinbart

, Stahl

, Klunk

, Yu

, Bird

(2010) Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133, 1143–1154.

Cruts

, Theuns

, Van Broeckhoven

(2012) Locus-specific mutation databases for neurodegenerative brain diseases. HumMutat 33, 1340–1344.

Newman

, Musgrave

, Lardelli

(2007) Alzheimer disease: Amyloidogenesis, the presenilins and animal models. Biochim Biophys Acta 3, 285–297.

Lai

M-T

, Chen

, Crouthamel

M-C

, DiMuzio-Mower

, Xu

, Huang

, Price

, Register

, Shi

X-P

, Donoviel

, Bernstein

, Hazuda

, Gardell

, Li

Y-M

(2003) Presenilin-1 and presenilin-2 exhibit distinct yet overlapping 7-secretase activities. J Biol Chem 278,22475–22481.

Lee

, Slunt

, Martin

, Thinakaran

, Kim

, Gandy

, Seeger

, Koo

, Price

, Sisodia

(1996) Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues. JNeurosci 16, 7513–7525.

Levy-Lahad

, Wasco

, Poorkaj

, Romano

, Oshima

, Pettingell

, Yu

, Jondro

, Schmidt

, Wang

, et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.

Finckh

, Alberici

, Antoniazzi

, Benussi

, Fedi

, Giannini

, Gal

, Nitsch

, Binetti

(2000) Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology 54, 2006–2008.

Ezquerra

, Lleo

, Castellvi

, Queralt

, Santacruz

, Pastor

, Molinuevo

, Blesa

, Oliva

(2003) A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease. ArchNeurol 60, 1149–1151.

10.

Ryman

, Acosta-Baena

, Aisen

, Bird

, Danek

, Fox

, Goate

, Frommelt

, Ghetti

, Langbaum

, Lopera

, Martins

, Masters

, Mayeux

, McDade

, Moreno

, Reiman

, Ringman

, Salloway

, Schofield

, Sperling

, Tariot

, Xiong

, Morris

, Bateman

(2014) Symptom onset in autosomal dominant Alzheimer disease: A systematic review and meta-analysis. Neurology 83, 253–260.

11.

Jayne

, Newman

, Verdile

, Sutherland

, Munch

, Musgrave

, Moussavi Nik

, Lardelli

(2016) Evidence for and against a pathogenic role of reduced gamma-secretase activity in familial Alzheimer’s disease. J Alzheimers Dis 52, 781–799.

12.

Sato

, Hori

, Yamaguchi

, Lambert

, Chartier-Harlin

, Robinson

, Delacourte

, Schmidt

, Furuyama

, Imaizumi

, Tohyama

, Takagi

(1999) A novel presenilin-2 splice variant in human Alzheimer’s disease brain tissue. J Neurochem 72, 2498–2505.

13.

Moussavi Nik

, Newman

, Wilson

, Ebrahimie

, Wells

, Musgrave

, Verdile

, Martins

, Lardelli

(2015) Alzheimer’s disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of gamma-secretase activity. Hum Mol Genet 24, 3662–3678.

14.

Steiner

, Fluhrer

, Haass

(2008) Intramembrane proteolysis by gamma-secretase. J Biol Chem 283,29627–29631.

15.

Shah

, Lee

, Tabuchi

, Hao

, Yu

, LaPlant

, Ball

, Dann

3rd , Sudhof

, Yu

(2005) Nicastrin functions as a gamma-secretase-substrate receptor. Cell 122, 435–447.

16.

Prokop

, Shirotani

, Edbauer

, Haass

, Steiner

(2004) Requirement of PEN-2 for stabilization of the pre-senilin N-/C-terminal fragment heterodimer within the 7-secretase complex. J Biol Chem 279, 23255–23261.

17.

Emilie

, Wu-Min

, Hui-Min

(2009) Aph-1 is required to regulate presenilin-mediated 7-secretase activity and cell survival in Drosophila wing development. Genesis 47, 169–174.

18.

Zhang

, Li

, Xu

, Zhang

(2014) The gamma-secretase complex: From structure to function. Front Cell Neurosci 8, 427.

19.

Cai

, An

, Kim

(2015) Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders. Clin Interv Aging 10, 1163–1172.

20.

Thinakaran

, Borchelt

, Lee

, Slunt

, Spitzer

, Kim

, Ratovitsky

, Davenport

, Nordstedt

, Seeger

, Hardy

, Levey

, Gandy

, Jenkins

, Copeland

, Price

, Sisodia

(1996) Endoproteolysis of prese-nilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181–190.

21.

Tomita

, Maruyama

, Saido

, Kume

, Shinozaki

, Tokuhiro

, Capell

, Walter

, Grünberg

, Haass

, Iwatsubo

, Obata

(1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid ß protein ending at the 42nd (or 43rd) residue. Proc Natl Acad Sci USA 94,2025–2030.

22.

De Strooper

, Annaert

, Cupers

, Saftig

, Craes-saerts

, Mumm

, Schroeter

, Schrijvers

, Wolfe

, Ray

, Goate

, Kopan

(1999) A presenilin-1-dependent [gamma]-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518522.

23.

Cao

, Sudhof

(2001) A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115–120.

24.

Placido

, Pereira

CMF

, Duarte

, Candeias

, Cor-reia

, Santos

, Carvalho

, Cardoso

, Oliveira

, Moreira

(2014) The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: Implications for Alzheimer’s disease. Biochim Biophys Acta 1842, 1444–1453.

25.

Thinakaran

, Koo

(2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283, 29615–29619.

26.

Zhang

Y-W

, Thompson

, Zhang

, Xu

(2011) APP processing in Alzheimer’s disease. Molecular Brain 4, 3.

27.

(2009) Gamma-secretase catalyzes sequential cleavages of the AbetaPP transmembrane domain. J Alzheimers Dis 16,211–224.

28.

Chavez-Gutierrez

, Bammens

, Benilova

, Vandersteen

, Benurwar

, Borgers

, Lismont

, Zhou

, Van Cley-nenbreugel

, Esselmann

, Wiltfang

, Serneels

, Karran

, Gijsen

, Schymkowitz

, Rousseau

, Broersen

, De Strooper

(2012) The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J 31, 2261–2274.

29.

Rezaei-Ghaleh

, Amininasab

, Kumar

, Walter

, Zweckstetter

(2016) Phosphorylation modifies the molecular stability of beta-amyloid deposits. Nat Commun 7, 11359.

30.

Fogel

, Frere

, Segev

, Bharill

, Shapira

, Gazit

, O'Malley

, Slomowitz

, Berdichevsky

, Walsh Dominic

, Isacoff Ehud

, Hirsch Joel

, Slutsky

(2014) APP homodimers transduce an amyloid-ß-mediated increase in release probability at excitatory synapses. Cell Reports 7, 1560–1576.

31.

Dolev

, Fogel

, Milshtein

, Berdichevsky

, Lipstein

, Brose

, Gazit

, Slutsky

(2013) Spike bursts increase amyloid-ß 40/42 ratio by inducing a presenilin-1 conformational change. Nat Neurosci 16, 587.

32.

Suzuki

, Cheung

, Cai

, Odaka

, Otvos

Jr. , Eckman

, Golde

, Younkin

(1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 1336–1340.

33.

Kuperstein

, Broersen

, Benilova

, Rozenski

, Jon-ckheere

, Debulpaep

, Vandersteen

, Segers-Nolten

, Van Der Werf

, Subramaniam

, Braeken

, Calle-waert

, Bartic

, D'Hooge

, Martins

, Rousseau

, Schymkowitz

, De Strooper

(2010) Neurotoxicity of Alzheimer’s disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO J 29, 3408–3420.

34.

Sun

, Zhou

, Yang

, Shi

(2017) Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase. Proc Natl Acad Sci USA 114, E476–E485.

35.

De Strooper

(2007) Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep 8, 141–146.

36.

Cacquevel

, Aeschbach

, Houacine

, Fraering

(2012) Alzheimer’s disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified gamma-secretase complexes. PLoS One 7,18.

37.

De Strooper

, Saftig

, Craessaerts

, Vanderstichele

, Guhde

, Annaert

, Von Figura

, Van Leuven

(1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390.

38.

Naruse

, Thinakaran

, Luo

, Kusiak

, Tomita

, Iwatsubo

, Qian

, Ginty

, Price

, Borchelt

, Wong

, Sisodia

(1998) Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, 1213–1221.

39.

Herreman

, Serneels

, Annaert

, Collen

, Schoon-jans

, De Strooper

(2000) Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol 2, 461–462.

40.

Zhang

, Nadeau

, Song

, Donoviel

, Yuan

, Bernstein

, Yankner

(2000) Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2, 463–465.

41.

Palacino

, Berechid

, Alexander

, Eckman

, Younkin

, Nye

, Wolozin

(2000) Regulation of amyloid precursor protein processing by presenilin 1 (PS1)and PS2 in PS1 knockout cells. J Biol Chem 275, 215–222.

42.

Shen

, Bronson

, Chen

, Xia

, Selkoe

, Tonegawa

(1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639.

43.

Herreman

, Hartmann

, Annaert

, Saftig

, Craes-saerts

, Serneels

, Umans

, Schrijvers

, Checler

, Vanderstichele

, Baekelandt

, Dressel

, Cupers

, Huylebroeck

, Zwijsen

, Van Leuven

, De Strooper

(1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci USA 96, 11872–11877.

44.

Pintchovski

, Schenk

, Basi

(2013) Evidence that enzyme processivity mediates differential Abeta pro-ductionby PS1 and PS2. Curr Alzheimer Res 10, 4–10.

45.

Yonemura

, Futai

, Yagishita

, Suo

, Tomita

, Iwatsubo

, Ishiura

(2011) Comparison of presenilin 1 and presenilin 2 gamma-secretase activities using a yeast reconstitution system. J Biol Chem 286, 44569–44575.

46.

Walker

, Martinez

, Brunkan

, Goate

(2005) Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Aß 42/40 ratios. J Neurochem 92, 294–301.

47.

Barucker

, Harmeier

, Weiske

, Fauler

, Albring

, Prokop

, Hildebrand

, Lurz

, Heppner

, Huber

, Multhaup

(2014) Nuclear translocation uncovers the amyloid peptide Abeta42 as a regulator of gene transcription. J Biol Chem 289, 20182–20191.

48.

Graff-Radford

, Crook

, Lucas

, Boeve

, Knop-man

, Ivnik

, Smith

, Younkin

, Petersen

, Younkin

(2007) Association of low plasma Aß42/Aß40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 64, 354–362.

49.

Jevtic

, Sengar

, Salter

, McLaurin

(2017) The role of the immune system in Alzheimer disease: Etiology and treatment. Ageing Res Rev 40, 84–94.

50.

Salter

, Beggs

(2014) Sublime microglia: Expanding roles for the guardians of the CNS. Cell 158, 15–24.

51.

Jayadev

, Case

, Eastman

, Nguyen

, Pollak

, Wiley

, Moller

, Morrison

, Garden

(2010) Presenilin 2 is the predominant gamma-secretase in microglia and modulates cytokine release. PLoS One 5, 0015743.

52.

Heneka

, Kummer

, Latz

(2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14, 463–477.

53.

Heneka

, Carson

, Khoury

, Landreth

, Brosseron

, Feinstein

, Jacobs

, Wyss-Coray

, Vitorica

, Ransohoff

, Herrup

, Frautschy

, Finsen

, Brown

, Verkhratsky

, Yamanaka

, Koistinaho

, Latz

, Halle

, Petzold

, Town

, Morgan

, Shi-nohara

, Perry

, Holmes

, Bazan

, Brooks

, Hunot

, Joseph

, Deigendesch

, Garaschuk

, Boddeke

, Dinarello

, Breitner

, Cole

, Golen-bock

, Kummer

(2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14, 388–405.

54.

Jayadev

, Case

, Alajajian

, Eastman

, Moller

, Garden

(2013) Presenilin 2 influences miR146 level and activity in microglia. J Neurochem 127, 592–599.

55.

Agrawal

, Sawhney

, Hickey

, McCarthy

(2016) Loss of presenilin 2 function is associated with defective LPS-mediated innate immune responsiveness. Mol Neu-robiol 53, 3428–3438.

56.

Donoviel

, Hadjantonakis

, Ikeda

, Zheng

, Hys-lop

, Bernstein

(1999) Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 13, 2801–2810.

57.

Kim

, Shen

(2008) Presenilins are required for maintenance of neural stem cells in the developing brain. Mol Neurodegener 3, 1750–1326.

58.

Louvi

, Artavanis-Tsakonas

(2006) Notch signalling in vertebrate neural development. Nat Rev Neurosci 7, 93–102.

59.

Shen

(2014) Function and dysfunction of presenilin. Neurodegener Dis 13, 61–63.

60.

Handler

, Yang

, Shen

(2000) Presenilin-1 regulates neuronal differentiation during neurogenesis. Development 127, 2593–2606.

61.

Brill

, Torchinsky

, Carp

, Toder

(1999) The role of apoptosis in normal and abnormal embryonic development. J Assist Reprod Genet 16, 512–519.

62.

Driver

, Beiser

, Au

, Kreger

, Splansky

, Kurth

, Kiel

, Lu

, Seshadri

, Wolf

(2012) Inverse association between cancer and Alzheimer’s disease: Results from the Framingham Heart Study. BMJ 12, e1442.

63.

Yun

, Park

, Kim

, Sung

, Lee

, Bae

, Hwang

(2016) Overexpression of N141I PS2 increases gamma-secretase activity through up-regulation of Presenilin and Pen-2 in brain mitochondria of NSE/hPS2m transgenic mice. Lab Anim Res 32, 249–256.

64.

Kovacs

, Mancini

, Henderson

, Na

, Schmidt

, Kim

, Tanzi

(1999) Staurosporine-induced activation of caspase-3 is potentiated by presenilin 1 familial Alzheimer’s disease mutations in human neuroglioma cells. J Neurochem 73, 2278–2285.

65.

Xia

, Qian

, Soriano

, Wu

, Fletcher

, Wang

, Koo

, Wu

, Zheng

(2001) Loss of prese-nilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci USA 98, 10863–10868.

66.

Serrano

, Fernandez

, Martinez-Murillo

, Martinez

(2010) High sensitivity to carcinogens in the brain of a mouse model of Alzheimer’s disease. Oncogene 29,2165–2171.

67.

Yun

, Park

, Kim

, Ahn

, Park

, Kim

, Yun

, Jung

, Hwang

, Yoon

, Han

, Hong

(2014) Loss of presenilin 2 is associated with increased iPLA2 activity and lung tumor development. Oncogene 33,5193–5200.

68.

Zhang

, Wang

, Liu

, Zhang

, Liao

, Xu

(2007) Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci USA 104, 10613–10618.

69.

Deng

, Pike

, Cotman

(1996) Alzheimer-associated presenilin-2 confers increased sensitivity to poptosis in PC12 cells. FEBS Lett 397, 50–54.

70.

Wolozin

, Iwasaki

, Vito

, Ganjei

, Lacana

, Sunderland

, Zhao

, Kusiak

, Wasco

, D'Adamio

(1996) Participation of presenilin 2 in apoptosis: Enhanced basal activity conferred by an Alzheimer mutation. Science 274, 1710–1713.

71.

Guo

, Christakos

, Robinson

, Mattson

(1998) Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: Reduced oxidative stress and preserved mitochondrial function. Proc Natl Acad Sci USA 95, 3227–3232.

72.

Suh

, Checler

(2002) Amyloid precursor protein, presenilins, and alpha-synuclein: Molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 54, 469–525.

73.

Park

, Yun

, Hwang

, Park

, Han

, Hwang

, Yoon

, Kim

, Hong

(2017) Presenilin mutation suppresses lung tumorigenesis via inhibition of peroxiredoxin 6 activity and expression. Theranostics 7, 3624–3637.

74.

Orr

, Oddo

(2013) Autophagic/lysosomal dysfunction in Alzheimer’s disease. Alzheimers Res Ther 5, 53.

75.

, Cuervo

, Kumar

, Peterhoff

, Schmidt

, Lee

, Mohan

, Mercken

, Farmery

, Tjernberg

, Jiang

, Duff

, Uchiyama

, Naslund

, Mathews

, Cataldo

, Nixon

(2005) Macroautophagy-a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 171,87–98.

76.

Nixon

, Wegiel

, Kumar

, Yu

, Peterhoff

, Cataldo

, Cuervo

(2005) Extensive involvement of autophagy in Alzheimer disease: An immuno-electron microscopy study. J Neuropathol Exp Neurol 64, 113–122.

77.

Lee

, Yu

, Kumar

, Lee

, Mohan

, Peterhoff

, Wolfe

, Martinez-Vicente

, Massey

, Sovak

, Uchiyama

, Westaway

, Cuervo

, Nixon

(2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158.

78.

Neely

, Green

, LaFerla

(2011) Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a gamma-secretase-independent manner. J Neurosci 31, 2781–2791.

79.

Coen

, Flannagan

, Baron

, Carraro-Lacroix

, Wang

, Vermeire

, Michiels

, Munck

, Baert

, Sugita

, Wuytack

, Hiesinger

, Grinstein

, Annaert

(2012) Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J Cell Biol 198, 23–35.

80.

Neely Kayala

, Dickinson

, Minassian

, Walls

, Green

, Laferla

(2012) Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: Implications for lysosomal function. Brain Res 13, 8–16.

81.

Sannerud

, Esselens

, Ejsmont

, Mattera

, Rochin

, Tharkeshwar

, De Baets

, De Wever

, Habets

, Baert

, Vermeire

, Michiels

, Groot

, Wouters

, Dillen

, Vints

, Baatsen

, Munck

, Derua

, Waelkens

, Basi

, Mercken

, Vooijs

, Bollen

, Schymkowitz

, Rousseau

, Bonifacino

, Van Niel

, De Strooper

, Annaert

(2016) Restricted location of PSEN2/gamma-secretase determines substrate specificity and generates an intracellular Abeta pool. Cell 166, 193208.

82.

Bissig

, Rochin

, van Niel

(2016) PMEL amyloid fibril formation: The bright steps of pigmentation. Int J Mol Sci 17, E1438.

83.

Jiang

, Newman

, Lardelli

(2018) The zebrafish orthologue of familial Alzheimer’s disease gene PRESENILIN 2 is required for normal adult melanotic skin pigmentation. PLoS One 13, e0206155.

84.

Querfurth

, Jiang

, Geiger

, Selkoe

(1997) Caffeine stimulates amyloid beta-peptide release from beta-amyloid precursor protein-transfected HEK293 cells. J Neurochem 69, 1580–1591.

85.

Mattson

, Guo

, Furukawa

, Pedersen

(1998) Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer’s disease. J Neurochem 70, 1–14.

86.

Disterhoft

, Moyer

Jr , Thompson

(1994) The calcium rationale in aging and Alzheimer’s disease. Evidence from an animal model of normal aging. Ann N Y Acad Sci 747, 382–406.

87.

Korol'

, Korol'

, Kostyuk

(2008) Disruption of calcium homeostasis in Alzheimer’s disease. Neurophysiology 40, 385–392.

88.

, Nelson

, Bezprozvanny

, Wang

, Lee

, Hao

, Serneels

, De Strooper

, Yu

, Bezprozvanny

(2006) Presenilins form ER Ca2+leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126, 981–993.

89.

Mattson

, Chan

, Camandola

(2001) Presenilin mutations and calcium signaling defects in the nervous and immune systems. BioEssays 23, 733–744.

90.

Leissring

, Parker

, LaFerla

(1999) Presenilin-2 mutations modulate amplitude and kinetics of inosi-tol 1,4,5-trisphosphate-mediated calcium signals. J Biol Chem 274, 32535–32538.

91.

Guo

, Furukawa

, Sopher

, Pham

, Xie

, Robinson

, Martin

, Mattson

(1996) Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide. Neuroreport 8, 379–383.

92.

Lafon-Cazal

, Pietri

, Culcasi

, Bockaert

(1993) NMDA-dependent superoxide production and neurotoxi-city. Nature 364, 535–537.

93.

Mattson

, Lovell

, Furukawa

, Markesbery

(1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J Neurochem 65, 1740–1751.

94.

Kruman

, Guo

, Mattson

(1998) Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J Neurosci Res 51, 293–308.

95.

Begley

, Duan

, Chan

, Duff

, Mattson

(1999) Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J Neurochem 72, 1030–1039.

96.

Pak

, Chan

, Mattson

(2003) Presenilin-1 mutation sensitizes oligodendrocytes to glutamate and amyloid tox-icities, and exacerbates white matter damage and memory impairment in mice. Neuromol Med 3, 53–64.

97.

Putney

Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7, 1–12.

98.

Leissring

, Akbari

, Fanger

, Cahalan

, Mattson

, LaFerla

(2000) Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 149, 793–798.

99.

Akbari

, Hitt

, Murphy

, Dagher

, Tseng

, Green

, Golde

, LaFerla

(2004) Presenilin regulates capacitative calcium entry dependently and independently of gamma-secretase activity. Biochem Biophys Res Commun 322, 1145–1152.

100.

Bandara

, Malmersjo

, Meyer

(2013) Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA. Sci Signal 6, 2003649.

101.

Kipanyula

, Contreras

, Zampese

, Lazzari

, Wong

, Pizzo

, Fasolato

, Pozzan

(2012) Ca2+ dysregu-lation in neurons from transgenic mice expressing mutant presenilin 2. Aging Cell 11, 885–893.

102.

Zampese

, Fasolato

, Kipanyula

, Bortolozzi

, Pozzan

, Pizzo

(2011) Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ crosstalk. Proc Natl Acad Sci USA 108, 2777–2782.

103.

Hroudova

, Singh

, Fisar

(2014) Mitochondrial dysfunctions in neurodegenerative diseases: Relevance to Alzheimer’s disease. Biomed Res Int 175062, 12.

104.

Moreira

, Carvalho

, Zhu

, Smith

, Perry

(2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta 1802, 2–10.

105.

Swerdlow

, Khan

(2004) A "mitochondrial cascade hypothesis" for sporadic Alzheimer’s disease. Med Hypotheses 63, 8–20.

106.

Swerdlow

, Khan

(2009) The Alzheimer’s disease mitochondrial cascade hypothesis: An update. Exp Neurol 218, 308–315.

107.

Behbahani

, Shabalina

, Wiehager

, Concha

, Hul-tenby

, Petrovic

, Nedergaard

, Winblad

, Cowburn

, Ankarcrona

(2006) Differential role of Presenilin-1 and -2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts. J Neurosci Res 84, 891–902.

108.

Contino

, Porporato

, Bird

, Marinangeli

, Opsomer

, Sonveaux

, Bontemps

, Dewachter

, Octave

, Bertrand

, Stanga

, Kienlen-Campard

(2017) Presenilin 2-dependent maintenance of mitochon-drial oxidative capacity and morphology. Front Physiol 8, 796.

109.

Hayashi

, Rizzuto

, Hajnoczky

, Su

(2009) MAM: More than just a housekeeper. Trends Cell Biol 19, 81–88.

110.

Csordas

, Varnai

, Golenar

, Roy

, Purkins

, Schneider

, Balla

, Hajnoczky

(2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39, 121–132.

111.

Rusinol

, Cui

, Chen

, Vance

(1994) A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains preGolgi secretory proteins including nascent lipoproteins. J Biol Chem 269, 27494–27502.

112.

Simmen

, Aslan

, Blagoveshchenskaya

, Thomas

, Wan

, Xiang

, Feliciangeli

, Hung

, Crump

, Thomas

(2005) PACS-2 controls endo-plasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24, 717–729.

113.

Area-Gomez

, de Groof

, Bonilla

, Montesinos

, Tanji

, Boldogh

, Pon

, Schon

(2018) A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis 9, 335.

114.

Hedskog

, Pinho

, Filadi

, Ronnback

, Hertwig

, Wiehager

, Larssen

, Gellhaar

, Sandebring

, Wester-lund

, Graff

, Winblad

, Galter

, Behbahani

, Pizzo

, Glaser

, Ankarcrona

(2013) Modulation of the endo-plasmic reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci USA 110, 7916–7921.

115.

Area-Gomez

, de Groof

, Boldogh

, Bird

, Gibson

, Koehler

, Yu

, Duff

, Yaffe

, Pon

, Schon

(2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol 175, 1810–1816.

116.

Pera

, Larrea

, Guardia-Laguarta

, Montesinos

, Velasco

, Agrawal

, Xu

, Chan

, Di Paolo

, Mehler

, Perumal

, Macaluso

, Freyberg

, Acin-Perez

, Enriquez

, Schon

, Area-Gomez

(2017) Increased localization of APP-C99 in mitochondria-associated ER membranes causes mito-chondrial dysfunction in Alzheimer disease. EMBO J 36, 3356–3371.

117.

de Brito

, Scorrano

(2008) Mitofusin 2 tethers endo-plasmic reticulum to mitochondria. Nature 456, 605–610.

118.

Filadi

, Greotti

, Turacchio

, Luini

, Pozzan

, Pizzo

(2016) Presenilin 2 modulates endoplasmic reticulum- mitochondria coupling by tuning the antagonistic effect of mitofusin 2. Cell Rep 15, 2226–2238.

119.

Area-Gomez

, Del Carmen Lara Castillo

, Tambini

, Guardia-Laguarta

, de Groof

, Madra

, Ike-nouchi

, Umeda

, Bird

, Sturley

, Schon

(2012) Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31, 4106–4123.

120.

Pluta

, Jablonski

, Ulamek-Koziol

, Kocki

, Brzozowska

, Januszewski

, Furmaga-Jablonska

, Bogucka-Kocka

, Maciejewski

, Czuczwar

(2013) Sporadic Alzheimer’s disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer’s disease genes. Mol Neurobiol 48, 500–515.

121.

Kim

, Basak

, Holtzman

(2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63, 287–303.

122.

Pluta

, Furmaga-Jablonska

, Maciejewski

, Ulamek-Koziol

, Jablonski

(2013) Brain ischemia activates beta- and gamma-secretase cleavage of amyloid precursor protein: Significance in sporadic Alzheimer’s disease. Mol Neurobiol 47, 425–434.

123.

Pluta

, Kocki

, Ulamek-Koziol

, Bogucka-Kocka

, Gil-Kulik

, Januszewski

, Jablonski

, Petniak

, Brzo-zowska

, Bogucki

, Furmaga-Jablonska

, Czuczwar

(2016) Alzheimer-associated presenilin 2 gene is dysreg-ulated in rat medial temporal lobe cortex after complete brain ischemia due to cardiac arrest. Pharmacol Rep 68, 155–161.

124.

Kocki

, Ulamek-Koziol

, Bogucka-Kocka

, Januszewski

, Jablonski

, Gil-Kulik

, Brzozowska

, Petniak

, Furmaga-Jablonska

, Bogucki

, Czuczwar

, Pluta

(2015) Dysregulation of amyloid-beta protein precursor, beta-secretase, presenilin 1 and 2 genes in the rat selectively vulnerable CA1 subfield of hippocampus following transient global brain ischemia. J Alzheimers Dis 47, 1047–1056.

125.

Sato

, Imaizumi

, Manabe

, Taniguchi

, Hitomi

, Katayama

, Yoneda

, Morihara

, Yasuda

, Takagi

, Kudo

, Tsuda

, Itoyama

, Makifuchi

, Fraser

, St George-Hyslop

, Tohyama

(2001) Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2. J Biol Chem 276, 2108–2114.

126.

Sharman

, Moussavi Nik

, Chen

, Ong

, Wijaya

, Laws

, Taddei

, Newman

, Lardelli

, Martins

, Verdile

(2013) The guinea pig as a model for sporadic Alzheimer’s disease (AD): The impact of cholesterol intake on expression of AD-related genes. PLoS One 8, e66235.

127.

Sciacca

, Ferri

, Licastro

, Veglia

, Biunno

, Gavazzi

, Calabrese

, Martinelli Boneschi

, Sorbi

, Mariani

, Franceschi

, Grimaldi

(2003) Interleukin-1B polymorphism is associated with age at onset of Alzheimer’s disease. Neurobiol Aging 24, 927–931.

128.

Ebrahimie

, Moussavi Nik

, Newman

, Van Der Hoek

, Lardelli

(2016) The zebrafish equivalent of Alzheimer’s disease-associated PRESENILIN isoform PS2V regulates inflammatory and other responses to hypoxic stress. J Alzheimers Dis 52, 581–608.

129.

Vina

, Lloret

(2010) Why women have more Alzheimer’s disease than men: Gender and mitochondrial toxicity of amyloid-beta peptide. J Alzheimers Dis 20, 2010–100501.

130.

Barnes

, Wilson

, Bienias

, Schneider

, Evans

, Bennett

(2005) Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 62, 685–691.

131.

Sinforiani

, Citterio

, Zucchella

, Bono

, Corbetta

, Merlo

, Mauri

(2010) Impact of gender differences on the outcome of Alzheimer’s disease. Dement Geriatr Cogn Disord 30, 147–154.

132.

Bowers

, Waddell

, McCarthy

(2010) A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol. Biol Sex Differ 1, 2042–6410.

133.

Thakur

, Ghosh

(2007) Age and sex dependent alteration in presenilin expression in mouse cerebral cortex. Cell Mol Neurobiol 27, 1059–1067.

134.

Ghosh

, Thakur

(2008) PS1 expression is downregu-lated by gonadal steroids in adult mouse brain. Neurochem Res 33, 365–369.

135.

Ghosh

, Thakur

(2008) PS2 protein expression is upregulated by sex steroids in the cerebral cortex of aging mice. Neurochem Int 52, 363–367.

136.

Drummond

, Martins

, Handelsman

, Harvey

(2012) Altered expression of Alzheimer’s disease-related proteins in male hypogonadal mice. Endocrinology 153, 2789–2799.

137.

Blauwendraat

, Wilke

, Jansen

, Schulte

, Simon-Sanchez

, Metzger

, Bender

, Gasser

, Maetzler

, Rizzu

, Heutink

, Synofzik

(2016) Pilot whole-exome sequencing of a German early-onset Alzheimer’s disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging 37, 208.e211–208.e217.

138.

Guerreiro

, Baquero

, Blesa

, Boada

, Bras

, Bullido

, Calado

, Crook

, Ferreira

, Frank

, Gomez-Isla

, Hernandez

, Lleo

, Machado

, Martinez-Lage

, Masdeu

, Molina-Porcel

, Molinuevo

, Pastor

, Perez-Tur

, Relvas

, Oliveira

, Ribeiro

, Rogaeva

, Sa

, Samaranch

, Sanchez-Valle

, Santana

, Tarraga

, Valdivieso

, Singleton

, Hardy

, Clarimon

(2010) Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging 31, 725–731.

139.

Sleegers

, Roks

, Theuns

, Aulchenko

, Rade-makers

, Cruts

, van Gool

, Van Broeckhoven

, Heutink

, Oostra

, van Swieten

, van Duijn

(2004) Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain 127, 1641–1649.

140.

Ertekin-Taner

, Younkin

, Yager

, Parfitt

, Baker

, Asthana

, Hutton

, Younkin

, Graff-Radford

(2008) Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. Neurology 70, 596–606.

141.

Brouwers

, Sleegers

, Van Broeckhoven

(2008) Molecular genetics of Alzheimer’s disease: An update. Ann Med 40, 562–583.

142.

Cruts

, van Duijn

, Backhovens

, Van den Broeck

, Wehnert

, Serneels

, Sherrington

, Hutton

, Hardy

, St George-Hyslop

, Hofman

, Van Broeck-hoven

(1998) Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 7, 43–51.

143.

Raciti

, Nicoletti

, Le Pira

, Andreoli

, Contrafatto

, Lanzafame

, Maci

, Gambardella

, Quattrone

, A Zappia

(2011) Presenilin-2 gene mutation presenting as Lewy Body dementia? Neurol Sci 32, 533–534.

144.

Gallo

, Tomaino

, Puccio

, Frangipane

, Curcio

, Bernardi

, Geracitano

, Anfossi

, Mirabelli

, Colao

, Vasso

, Smirne

, Maletta

, Bruni

(2010) Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. Neurol Sci 31, 65–70.

145.

Dobricic

, Stefanova

, Jankovic

, Gurunlian

, Novakovic

, Hardy

, Kostic

, Guerreiro

(2012) Genetic testing in familial and young-onset Alzheimer’s disease: Mutation spectrum in a Serbian cohort. Neurobiol Aging 33, 4.

146.

Piscopo

, Talarico

, Malvezzi-Campeggi

, Crestini

, Rivabene

, Gasparini

, Tosto

, Vanacore

, Lenzi

, Bruno

, Confaloni

(2011) Presenilin 2 mutation R71W in an Italian early-onset sporadic Alzheimer’s disease case. J Neurol 258, 2043–2047.

147.

Shi

, Wang

, Liu

, Zhou

, Wang

, Cai

, Huo

, Gao

, Ji

(2015) Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord 39, 32–40.

148.

Piscopo

, Marcon

, Piras

, Crestini

, Campeggi

, Deiana

, Cherchi

, Tanda

, Deplano

, Vanacore

, Tagliavini

, Pocchiari

, Giaccone

, Confaloni

(2008) A novel PSEN2 mutation associated with a peculiar phenotype. Neurology 70, 1549–1554.

149.

Finckh

, Muller-Thomsen

, Mann

, Eggers

, Marksteiner

, Meins

, Binetti

, Alberici

, Hock

, Nitsch

, Gal

(2000) High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 66, 110–117.

150.

Finckh

, Kuschel

, Anagnostouli

, Patsouris

, Pantes

, Gatzonis

, Kapaki

, Davaki

, Lamszus

, Stavrou

, Gal

(2005) Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics 6, 85–89.

151.

Binetti

, Signorini

, Squitti

, Alberici

, Benussi

, Cassetta

, Frisoni

, Barbiero

, Feudatari

, Nicosia

, Testa

, Zanetti

, Gennarelli

, Perani

, Anchisi

, Ghidoni

, Rossini

(2003) Atypical dementia associated with a novel presenilin-2 mutation. Ann Neurol 54, 832–836.

152.

Xia

, Chen

, Shi

, Huang

, Xu

, Zhao

, He

, Wu

, Xu

, Zang

, Zhang

(2015) Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer’s disease. Neurobiol Aging 36, 3334.e13–3334.e18.

153.

Muller

, Winter

, Bolender

, Nolte

(2014) Previously unrecognized missense mutation E126K of PSEN2 segregates with early onset Alzheimer’s disease in a family. J Alzheimers Dis 42, 109–113.

154.

Tomaino

, Bernardi

, Anfossi

, Costanzo

, Ferrise

, Gallo

, Geracitano

, Maletta

, Curcio

, Mirabelli

, Colao

, Frangipane

, Puccio

, Calignano

, Muraca

, Paonessa

, Smirne

, Leotta

, Bruni

(2007) Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer’s disease J Neurol 254, 391–393.

155.

, Parks

, Kushner

, Nauman

, Burgess

, Ludwigsen

, Partain

, Nixon

, Allen

, Irwin

, Jakobs

, Litt

, Hershberger

(2006) Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet 79, 1030–1039.

156.

Bernardi

, Tomaino

, Anfossi

, Gallo

, Geracitano

, Puccio

, Colao

, Frangipane

, Mirabelli

, Smirne

, Giovanni Maletta

, Bruni

(2008) Late onset familial Alzheimer’s disease: Novel presenilin 2 mutation and PS1 E318G polymorphism. J Neurol 255, 604–606.

157.

Niu

, Yu

, Zhang

, Yi

, Ye

, Tang

, Qiu

, Wen

, Sun

, Gao

, Guo

(2014) Novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer’s disease in a Chinese Han family. Neurobiol Aging 35, 18.

158.

Rogaev

, Sherrington

, Rogaeva

, Levesque

, Ikeda

, Liang

, Chi

, Lin

, Holman

, Tsuda

, et al. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778.

159.

Lao

, Beyer

, Fernandez-Novoa

, Cacabelos

(1998) A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer’s disease. Neurogenetics 1, 293–296.

160.

Wallon

, Rousseau

, Rovelet-Lecrux

, Quillard-Muraine

, Guyant-Marechal

, Martinaud

, Pariente

, Puel

, Rollin-Sillaire

, Pasquier

, Le Ber

, Sarazin

, Croisile

, Boutoleau-Bretonniere

, Thomas-Anterion

, Paquet

, Moreaud

, Gabelle

, Sellal

, Sauvee

, Laquerriere

, Duyckaerts

, Delisle

, Streichen-berger

, Lannes

, Frebourg

, Hannequin

, Campion

(2012) The French series of autosomal dominant early onset Alzheimer’s disease cases: Mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis 30, 847856.

161.

Puschmann

, Ross

, Vilarino-Guell

, Lincoln

, Kachergus

, Cobb

, Lindquist

, Nielsen

, Wszolek

, Farrer

, Widner

, van Westen

, Hagerstrom

, Markopoulou

, Chase

, Nilsson

, Reimer

, Nilsson

(2009) A Swedish family with de novo alpha-synuclein A53T mutation: Evidence for early cortical dysfunction. Parkinsonism Relat Disord 15, 627–632.

162.

Lohmann

, Guerreiro

, Erginel-Unaltuna

, Gurunlian

, Bilgic

, Gurvit

, Hanagasi

, Luu

, Emre

, Singleton

(2012) Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging 33, 13.

163.

Piscopo

, Talarico

, Crestini

, Gasparini

, Malvezzi-Campeggi

, Piacentini

, Lenzi

, Bruno

, Confaloni

(2010) A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer’s disease. J Alzheimers Dis 20, 43–47.

164.

Marin-Munoz

, Noguera-Perea

, Gomez-Tortosa

, Lopez-Motos

, Antequera-Torres

, Martinez-Herrada

, Manzanares-Sanchez

, Vivancos-Moreau

, Legaz-Garcia

, Rabano-Gutierrez Del Arroyo

, Antunez-Almagro

(2016) Novel mutation (Gly212Val) in the PS2 gene associated with early-onset familial Alzheimer’s disease. J Alzheimers Dis 53, 73–78.

165.

Youn

, Bagyinszky

, Kim

, Choi

, An

, Kim

(2014) Probable novel PSEN2 Val214Leu mutation in Alzheimer’s disease supported by structural prediction. BMC Neurol 14, 1471–2377.

166.

Zekanowski

, Styczynska

, Peplonska

, Gabryelewicz

, Religa

, Ilkowski

, Kijanowska-Haladyna

, Kotapka-Minc

, Mikkelsen

, Pfeffer

, Barczak

, Luczywek

, Wasiak

, Chodakowska-Zebrowska

, Gustaw

, Laczkowski

, Sobow

, Kuznicki

, Bar-cikowska

(2003) Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer’s disease in Poland. Exp Neurol 184, 991–996.

167.

Marcon

, Di Fede

, Giaccone

, Rossi

, Giovagnoli

, Maccagnano

, Tagliavini

(2009) A novel Italian presenilin 2 gene mutation with prevalent behavioral phenotype. J Alzheimers Dis 16, 509–511.

168.

Lee

, Kahn

, Cheng

, Reitz

, Vardarajan

, Lan-tigua

, Medrano

, Jimenez-Velazquez

, Williamson

, Nagy

, Mayeux

(2014) Disease-related mutations among Caribbean Hispanics with familial dementia. Mol Genet Genomic Med 2, 430–437.

169.

Sassi

, Guerreiro

, Gibbs

, Ding

, Lupton

, Troakes

, Al-Sarraj

, Niblock

, Gallo

, Adnan

, Killick

, Brown

, Medway

, Lord

, Turton

, Bras

, Morgan

, Powell

, Singleton

, Hardy

(2014) Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer’s disease. Neurobiol Aging 35, 16.

170.

Marcon

, Giaccone

, Cupidi

, Balestrieri

, Beltrami

, Finato

, Bergonzi

, Sorbi

, Bugiani

, Tagliavini

(2004) Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol 63, 199–209.

171.

Lleo

, Castellvi

, Blesa

, Oliva

(2002) Uncommon polymorphism in the presenilin genes in human familial Alzheimer’s disease: Not to be mistaken with apathogenic mutation. Neurosci Lett 318, 166–168.

172.

Lindquist

, Hasholt

, Bahl

, Heegaard

, Andersen

, Norremolle

, Stokholm

, Schwartz

, Batbayli

, Laursen

, Pardossi-Piquard

, Chen

, St George-Hyslop

, Waldemar

, Nielsen

(2008) A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment. Eur J Neurol 15, 1135–1139.

173.

Yagi

, Miyamoto

, Morino

, Izumi

, Kuramochi

, Kurashige

, Maruyama

, Mizuno

, Kurihara

, Kawakami

(2014) Detecting gene mutations in Japanese Alzheimer’s patients by semiconductor sequencing. Neurobiol Aging 35, 25.

174.

Lleo

, Blesa

, Queralt

, Ezquerra

, Molinuevo

, Pena-Casanova

, Rojo

, Oliva

(2002) Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol 59, 1759–1763.

175.

Lleo

, Blesa

, Gendre

, Castellvi

, Pastor

, Queralt

, Oliva

(2001) A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer’s disease. Neurology 57, 1926–1928.