Understanding Changes in Hippocampal Interneurons Subtypes in the Pathogenesis of Alzheimer's Disease: A Systematic Review

Abstract

Background:

It is becoming increasingly recognized that there is significant interneuron degeneration in Alzheimer's disease. As the hippocampus is integral for learning and memory, we performed a systematic review of primary literature focused on the relationship between Alzheimer's and hippocampal interneurons. In this study, we summarize the experimental work performed to date and identify opportunities for future experiments.

Objectives:

This PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-style systematic review seeks to summarize the findings of all accessible research focused on cholecystokinin (CCK), neuropeptide Y (NPY), parvalbumin (PV), and somatostatin (SOM) interneurons in the hippocampal formation.

Results:

One thousand five hundred ninety-three articles were pulled from PubMed, PsycInfo, and Web of Science, based on three blocks of search terms. There were 45 articles that met all the predetermined inclusion/exclusion criteria. There is strong evidence that PV interneurons are affected early in the disease by toxic amyloid beta (Aβ) fragments; SOM interneurons are affected indirectly while the SOM neuropeptide may act to slowly worsen toxic Aβ fragment accumulation, whereas NPY- and CCK-positive interneurons are affected later in the progression of the disease.

Conclusions:

Fewer studies have been performed on NPY and CCK interneurons, and there is room for further investigations regarding the role of PV interneurons in Alzheimer's to help resolve contradictory findings. This review found that PV interneurons are affected early in the disease, but only in Alzheimer's precursor protein but not tau models. NPY and CCK interneurons were found to be affected later in the disease, and SOM interneurons vary greatly. Future studies may consider reporting immunohistochemical studies inclusive of either cell location or morphology—as well as marker to give a more robust picture of the disease.

Impact statement

In the past decade, the contribution of hippocampal interneurons to the pathology of Alzheimer's disease has been increasingly recognized. The goal of this systematic review was to summarize findings to better determine the focus of the work to date, to help identify where there is consensus in the research, and to elucidate future avenues of inquiry.

Introduction

Alzheimer's disease (AD) is a debilitating neuropathology that is becoming increasingly prevalent in modern societies of aging population (Ballard et al., 2011; Patterson, 2018). According to the 2018 World Alzheimer's Report, more than 50 million people are affected, and the global cost exceeds 1 trillion dollars (Patterson, 2018). Our understanding of AD pathology has advanced recently to shift from a focus on tau and amyloid beta (Aβ) in principal neurons to the roles they may play in altering interneurons (Najm et al., 2019; Rozycka and Liguz-Lecznar, 2017; Solarski et al., 2018; Verret et al., 2012; Vico Varela et al., 2019). The systematic nature of this review will add to the field by summarizing knowledge about how different interneuron subtypes contribute to the pathology of AD and, more importantly, by determining areas that could benefit from replication, where there is a lack of consensus, as well as identifying knowledge gaps in the current literature. This review includes work performed in mouse, rat, and human studies that focus on questions directly related to the relationship between interneurons and AD in the hippocampal formation.

It is well established that dysfunction in the structure and metabolism of tau and Alzheimer's precursor protein (APP) are strongly associated with AD, and this has led to the theory that an initial dysregulation of APP metabolism causes toxic Aβ to accumulate and leads to the aggregation of phosphorylated tau neurofibrillary tangles and neurodegeneration (Bloom, 2014). Recently, it has been discovered that APP dysregulation seems to affect interneurons initially, leading to speculation that the loss of interneurons could then cause aberrant neural activity and excitotoxicity in principal cells (Kiss et al., 2016; Palop et al., 2007). As this degeneration progresses regionally, the circuit changes can also affect cortical and basal brain regions differently (Fewster et al., 1991). Interneuron subtypes can be segregated immunohistochemically in the hippocampus, with antibodies specific for parvalbumin (PV), somatostatin (SOM), cholecystokinin (CCK), or neuropeptide Y (NPY) being the main ways used to differentiate these populations (Pelkey et al., 2017). While calretinin and calbindin are also markers assessed in interneurons, these markers are expressed across a wider variety of interneurons and not considered as their own distinct subclasses (Rogers, 1987). For the purpose of this review, hippocampal interneuron subtypes were simplified as immunohistochemically defined. A strength of immunohistochemical studies is that studies in postmortem human tissue may be included. This allows for parallels to be drawn between mice and rats exposed to specific homogeneous disease conditions and the clinical population. Immunohistochemical studies, however, are often limited by the lack of ability to view changes over time or in three dimensions. In rodent studies, optogenetics and whole-brain clearing with sheet fluorescence confocal microscopy can be used to overcome this. From a technical standpoint, immunohistochemical studies must be carefully validated; antibody cross-reactivity and specificity can make cells erroneously appear positive for a marker while darkness of staining between replicates must be kept constant for accurate evaluation.

CCK was first discovered as a digestive hormone; however, it is also a specific marker for interneurons in the hippocampus. CCK has two main G-protein-coupled receptors: CCKAR and CCKBR (Nishimura et al., 2015). CCKBR is the predominant receptor in the brain, and the activation of this signal cascade has been linked to anxiety-like behavior (Nishimura et al., 2015; Singh et al., 1991). CCK-positive interneurons colocalize with the cannabinoid receptor type 1 (CB1) and likely play an important role in the interaction between delta-9-tetrahydrocannabinol (THC) consumption and AD (Lee and Soltesz, 2011). There is an abundance of articles that assess cannabis and cannabis-derived compounds as a potential treatment for AD (Aso et al., 2015; Brown University, 2019; Janefjord et al., 2014; Li et al., 2020; Shelef, et al., 2016). Two main potential mechanisms have been identified. The first is through G_i/o-linked CB1 receptors that are primarily located in the hippocampus on CCK-positive interneurons. Effects have also been associated with cannabinoid receptor type 2 (CB2) receptors, which are more prevalent on astrocytes and in the peripheral nervous system (Scheyer et al., 2019). To date, there is a lack of consensus on whether cannabis treatment is helpful or harmful, with studies varying greatly across exposure paradigms; see Charernboon and colleagues (2021) for a systematic review on treatment outcomes. Regardless of whether cannabis is effective for treating AD, CB1 receptor activation causes a signal cascade that inhibits neurotransmitter release (i.e., GABA in CCK interneurons) (Scheyer et al., 2019). CCK-positive interneurons are therefore necessary to consider when assessing inhibition/excitation imbalance in AD.

NPY also has functions as a gastric hormone as well as a neuro-signaling molecule (Sundler et al., 1983). In the brain, NPY acts upon a host of postsynaptic G-protein-coupled receptors (Duarte-Neves et al., 2016). NPY-positive interneurons have been implicated in adult neurogenesis, a mechanism that is thought to occur in the dentate gyrus (DG) (Decressac et al., 2009). Adult neurogenesis is the process of new granule cell growth from a pool of neural stem cells, and this is thought to be integral to memory consolidation (Snyder, 2019). NPY has been shown to increase neural precursor proliferation, and the number of NPY-positive interneurons has been shown to decline from young adulthood to middle age (Hattiangady et al., 2005; Spencer et al., 2016). NPY has also been implicated in post-traumatic stress disorder, Huntington's disease, and epilepsy (Schmeltzer et al., 2016; Wagner et al., 2016; Wickham et al., 2019).

PV is a calcium binding protein, and changes in PV affect presynaptic calcium signaling (Collin et al., 2005). Calcium signaling is a driving force behind neurotransmitter release, and the amount of time that calcium is able to bind to its ligands helps determine neuronal signal fidelity (Branch et al., 2014). PV-containing basket interneurons make up 15% of all interneurons in the CA1 hippocampal subregion (Pelkey et al., 2017). PV-containing basket cells are associated with both theta and gamma waves in the hippocampus, although they preferentially act in gamma oscillations (Chung et al., 2020). They are thought to be integral to lateral inhibition, memory consolidation, and made up the bulk of the results in the articles that we identified (Espinoza et al., 2018; Ognjanovski et al., 2017). PV interneurons are implicated in the seizure component of AD, and some studies have found these cells to decrease in number over time (Albuquerque et al., 2015; Hijazi et al., 2019; Mahar et al., 2017).

SOM was first discovered in the pituitary, and while it is expressed on GABAergic neurons, there was debate as to the function of SOM itself (Boehm and Betz, 1997; Brazeau et al., 1973). There are five SOM receptors, four of which have been found in the hippocampus (Cammalleri et al., 2019). SOM receptors are all G-protein-coupled receptors and can be found pre- and postsynaptic (Cammalleri et al., 2019; Hoyer et al., 1995). SOM signaling acts as an inhibitory molecule through action on potassium channels, leading to hyperpolarization of the postsynaptic neuron (Schweitzer et al., 1998). SOM-positive interneurons act in the creation of theta oscillations, have been found to be decreased in AD brains, and tend to be found in the stratum oriens lacunosum moleculare layer in the hippocampus (Chung et al., 2020; Schmid et al., 2016). Recent studies have shown that they accumulate phosphorylated tau, and new evidence suggests that they facilitate hippocampal–prefrontal synchrony and spatial encoding (Abbas et al., 2018; Zheng et al., 2020).

Here, we use a modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline to review the literature published on SOM-, PV positive, CCK-, and NPY-positive interneurons in the hippocampus in relation to the cellular pathogenesis of AD in the hippocampus.

Methods

This review was completed under the stylistic criteria of the PRISMA. Minor revisions were made to the traditional process due to the nature of cellular studies (e.g., exclusion of bias scoring) as reported by Moher and colleagues (2009). In lieu of bias scoring, articles that recommended a treatment were excluded. PRISMA search terms were designed to capture all articles that discussed hippocampal CCK, SOM, NPY, or PV interneurons and AD, and then, articles were selected based on the inclusion and exclusion criteria (Supplementary Table S2). Within search blocks, similar terms were grouped using “OR” as an operator, and between search blocks an “AND” operator was used. Three blocks of search terms were used. Blocks of search terms required articles to (1) mention interneurons, (2) mention the hippocampus, and (3) specify Alzheimer's Disease or Dementia (Supplementary Table S3). The search was completed in three databases, PubMed, PsycINFO, and Web of Science, by two authors individually using the same terms. Dates of coverage for the search included January 1, 2000–June 15, 2020. Citations were all exported to Mendeley, duplicates were removed, and articles were screened using the inclusion/exclusion criteria (Supplementary Table S2). Initially, titles and abstracts were screened, and if the article showed potential relevance, the article was read in full. Final articles were compared between the two authors, and discrepancies were resolved through discussion. A forward and reverse search was completed from the selected articles' reference lists to identify any additional relevant articles.

Results

Figure 1 summarizes the selection process. A total of 1598 records were identified through database searching and additional sources. We identified 73 records after review of title and abstract at an initial screening. Twenty-eight of these records were then excluded after full-text article screening as 10 records did not study solely AD model or include an AD model, 12 did not study CCK, PV, SOM, or NPY interneurons, 3 were not in the hippocampus, 2 were not research articles, and 1 used a treatment. These excluded articles are referenced in Supplementary Table S1. Forty-five articles met the inclusion criteria and were included in the qualitative analysis. The number of studies found to analyze CCK, NPY, PV, and SOM hippocampal interneurons was 5, 10, 37, and 20, respectively. Of these 45 articles, 5 studied human AD subjects, 6 studied rat AD models, and 36 studied mice AD models. All the five human AD studies used both male and female subjects. Of the 36 mice studies, 15 studies were on male mice, 1 study was on females, 8 studies included both sexes, and 12 studies did not specify sex. Four of the AD rat studies included only male rats, whereas two studies included only female rats (Supplementary Table S4).

FIG. 1.

PRISMA flow diagram for the selection of articles included in this systematic review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2 shows that most studies identified were performed in mice, and that most studies were sex-balanced. Studies with “Unspecified” as sex were almost completely mouse studies and were likely sex-balanced as well. Figure 3 panels show the types of assay performed in each cell type, and the colour of the bar indicates if the finding was an increase, decrease, or null finding from baseline. For the purpose of bucketing results, experiments that used multiple markers (of the main four investigated), experiments that validated a method, and duplicate experiments between a hippocampal region and subfield were excluded from this figure.

FIG. 2.

Breakdown of sex and species used in the 45 articles included in this systematic review.

FIG. 3.

Summary of experimental findings across all articles included in the study showing agreement or disagreement in the literature.

Cholecystokinin

Five articles were found to focus on CCK hippocampal interneurons. The distribution of species and sex studied is listed in Table 1. Three articles assessed CCK immunoreactivity in the hippocampus. Two of these articles showed no change in CCK-positive cells after Aβ injections (Aguado-Llera et al., 2018; Villette et al., 2012), whereas the other article showed a decrease in CCK-positive cells only at 4 months and 9–18 months (Shi et al., 2020). Similarly, two articles assessed CCK mRNA content in the hippocampus and found no change in PS1xAPP mice (Ramos et al., 2006) or in rats after a 14 day infusion of Aβ25–35 (Aguado-Llera et al., 2018). One study assessed Aβ accumulation in CCK interneurons and found an age-dependent increase from 9 to 18 months in APP^NL-F/NL-F mice (Shi et al., 2020). Finally, one study found that CCK-8S administration into an AD mouse model increased the spine density of hippocampal neurons (Zhang et al., 2013). This work showed that three of the five articles found evidence that hippocampal interneurons are not affected until older age in animal models.

Table 1.

Summary of Cholecystokinin Experiments in Identified Literature

	Year	Species	Sex	Assay type	Region	Finding
Villette et al.	2012	Rat	M	Immuno	CA1	No change in hippocampal amyloid deposits or change in density 24 days after Aβ40 and Aβ42 injection into dorsal hippocampus
Zhang et al.	2013	Mouse	U	Immuno	H	Significant increase in density of filopodia and spines at DIV 7, DIV 14, and DIV 21, similar to WT levels
Zhang et al.	2013	Mouse	U	Immuno	H	CI988 significantly inhibited the effect of CCK-8S on density of filopodia and spines in both WT and APP/PS1 neurons
Ramos et al.	2006	Mouse	M	RNA extraction	H	No reduction in CCK mRNA in 6-month-old APPxPS1 mice compared with WT
Shi et al.	2020	Mouse	M	Immuno	CA1	Accumulation of Aβ seen at 9–18 months of age in APP^NL-F/NL-F mice
Shi et al.	2020	Mouse	M	Immuno	CA1	Loss of cell density in APP^NL-F/NL-F mice compared with WT at 4 months and 9–18 months but not at 1–3 months
Aguado-Llera et al.	2018	Rat	M	Immuno	H	No change in CCK cell density after 14 day Aβ25–35 infusion into right cerebral ventricle
Aguado-Llera et al.	2018	Rat	M	RT-PCR	CA1	No change in CCK mRNA after 14 day Aβ25–35 infusion into right cerebral ventricle

Aβ, amyloid beta; APP, Alzheimer's precursor protein; CCK, cholecystokinin; H, hippocampus; M, male; RT-PCR, reverse-transcriptase PCR; U, unspecified; WT, wild type.

Neuropeptide Y

To better understand the role of NPY interneurons in AD, we assessed articles that examined hippocampal NPY interneurons in rat and mice AD models. No studies were found to assess human AD tissue. The distribution of species and sex studied is listed in Table 2. Seven articles assessed the immunoreactivity of NPY in various layers and regions of the hippocampus in AD, and six of these articles showed decreased NPY immunoreactivity in AD models (Albuquerque et al., 2015; Leung et al., 2012; Loreth et al., 2012; Mahar et al., 2017; Moreno-Gonzalez et al., 2009; Ramos et al., 2006). Specifically, three articles discovered decreased NPY immunoreactivity in the CA1, CA2, and DG regions of mouse AD models at 1 month (Mahar et al., 2017), 6 months (Albuquerque et al., 2015), and 12 and 18 months (Loreth et al., 2012). One article did not observe any change to NPY immunoreactivity in the CA1 region 24 days after microinjection of Aβ40 and Aβ45 compared with controls (Villette et al., 2012), whereas another article did not observe any change in the subiculum region at 6 months in a mouse AD model (Albuquerque et al., 2015). One study focused on the entorhinal cortex region and found decreased NPY immunoreactivity in PS1xAPP mice at 6 months compared with controls (Moreno-Gonzalez et al., 2009).

Table 2.

Summary of Neuropeptide Y Experiments in Identified Literature

	Year	Species	Sex	Assay type	Region	Finding
Villette et al.	2012	Rat	M	Immuno	CA1	No change in NPY density 24 days after amyloid injections
Villette et al.	2012	Rat	M	Immuno	CA1	No change in NPY/SOM density 24 days after amyloid injections
Palop et al.	2007	Mouse	U	Immuno	DG	Tau removal prevented NPY increases caused by kainate injection
				RT-PCR	DG	NPY-Y1 receptor mRNA level decreased and NPY-Y2 receptor mRNA level increased in hAPP-J20 mice compared with WT
				Immuno	DG	Increased NPY expression in hAPP_FAD mice compared with NTG and hAPP_WT. No correlation with NPY expression and amyloid load
Ghosal and Pimplikar	2011	Mouse	U	Immuno	DG	No change in NPY levels compared with controls in the molecular layer of AICD transgenic mice
Leung et al.	2012	Mouse	F	Immuno	Hi	No change in NPY levels among apoE isoforms. apoE-KI Fs had higher NPY levels than apoE-KI Ms at 1 month and decreased with aging
			F	MWM	Hi	No correlation with NPY+ interneurons and spatial learning
			M	Immuno	Hi	No change in NPY levels among apoE isoforms. apoE-KI Ms had lower NPY levels than apoE-KI Fs at 1 month and increased with aging
			M	MWM	Hi	No correlation with NPY and spatial learning
Ramos et al.	2006	Mouse	M	RNA extraction	H	Decreased NPY mRNA expression by hippocampal neurons 6-month-old PS1xAPP mice compared with WT
Ramos et al.	2006	Mouse	M	Immuno	H	Decreased cell number at 6 months of age in PS1xAPP mice compared with WT or PS1 mice
Moreno-Gonzalez et al.	2009	Mouse	U	Immuno	EC	Decreased SOM and NPY cells in the EC of PS1xAPP mice at 6 months of age. Extracellular APP was more toxic than intracellular
Mahar et al.	2017	Mouse	M	Immuno	CA1/2	Overall decrease of NPY cells in 1-month-old TgCRND8 mice compared with WT. No change in m.o., decreased in p.o., decreased in s.o., no change in s.r.
					CA3	No change in NPY cell density in 1-month-old TgCRND8 mice compared with WT
					DG	Overall decrease in NPY cell density in 1-month-old TgCRND8 mice compared with WT. Decreased in g.r., no change in m.o., decreased in p.o.
					H	Decrease in NPY cell density in 1-month-old TgCRND8 mice compared with WT
					Sub	No change
Albuquerque et al.	2015	Mouse	M	Immuno	CA1/2	Decreased cells in 6-month-old TgCRND8 mice compared with controls. No change in m.o., decrease in p.y., decrease in s.o., decrease in s.r.
					CA3	Decreased cells in 6-month-old TgCRND8 mice compared with controls. No change in p.y., decrease in s.o., no change in s.r.
					DG	Decreased cells in 6-month-old TgCRND8 mice compared with controls. No change in g.r., no change in m.o., decrease in p.o.
					H	Decrease in cells/slice in 6-month-old TgCRND8 mice compared with controls
					Sub	No change in cells/slice in 6-month-old TgCRND8 mice compared with controls
Loreth et al.	2012	Mouse	U	Immuno	CA1–3	Decreased at 12 and 18 months in TauPS2APP mice compared with WT
					DG	Decreased at 12 and 18 months in TauPS2APP mice compared with WT
					Hi	Decreased at 12 and 18 months in TauPS2APP mice compared with WT
Aguado-Llera et al.	2018	Rat	M	RT-PCR	H	Decreased NPY mRNA after Aβ25–35 infusion increased NPY mRNA after IGF-I and Aβ25–35 co-administration, and IGF-I alone compared with controls

AICD, amyloid precursor protein intracellular domain; DG, dentate gyrus; EC, entorhinal cortex; F, female; g.r., granule cell layer; Hi, hilus; m.o., molecular layer; NPY, neuropeptide Y; p.o.; p.y.; s.o., stratum oriens; SOM, somatostatin; s.r, stratum radiatum.

Corresponding to decreased NPY immunoreactivity, two articles analyzed NPY mRNA levels in the hippocampus of AD mice and found that these were decreased compared with controls after a 14 day Aβ25–35 infusion into the hippocampus (Aguado-Llera et al., 2018) or in 6-month-old PS1xAPP mice (Ramos et al., 2006). However, one of these articles found that co-administration of IGF-1 with Aβ25–35 restored the reduction of NPY mRNA (Aguado-Llera et al., 2018). There were two studies that assessed NPY receptor levels in AD mice, and one of these articles found no change in NPY receptor levels compared with controls (Ghosal and Pimplikar, 2011), whereas the other study found that NPY-Y1 receptor mRNA levels were decreased, but NPY-Y2 receptor mRNA levels were increased in hAPP-J20 mice compared with wild-type (WT) controls (Palop et al., 2007). Interestingly, one article found that AD mice that expressed higher levels of activity-related cytoskeleton protein (Arc) also had higher NPY levels (Palop, et al., 2007). The majority of studies here support the conclusion that NPY levels are reduced with AD pathology.

Parvalbumin

A total of 37 articles that assessed PV hippocampal interneurons in AD were evaluated. The distribution of species and sex studied is listed in Table 3. Twenty-one articles used immunohistochemistry to quantify the changes seen in PV interneuron levels of various AD models in various regions and layers of the hippocampus. Nine of these articles found a decrease in PV immunoreactivity compared with controls (Ahnaou et al., 2017; Aso et al., 2018; Hoefling et al., 2019; Huh et al., 2016; Levenga et al., 2013; Popovic et al., 2008; Soler et al., 2017; Takahashi et al., 2010; Zallo et al., 2018), two articles found an increase in PV immunoreactivity (Hollnagel et al., 2019; Verdaguer et al., 2015), and five articles found no change compared with controls (Albuquerque et al., 2015; Moreno-Gonzalez et al., 2009; Ramoset al., 2006; Villette et al., 2012; Waller et al., 2020); however, this was not taking into account the specific region within the hippocampus. Additionally, five articles found increases, decreases, or null effects in PV positive cell density depending on the particular hippocampal region studied or the time period assessed (Arevalo-Serrano et al., 2008; Hijazi et al., 2019; Loreth et al., 2012; Mahar et al., 2017; Petrache et al., 2019). For example, one study found no change in the CA1 region of a mouse AD model but found decreased PV positive cell density in the dorsal lateral entorhinal cortex (Petrache et al., 2019). Another article reported decreased PV positive cell density in the CA1 but no change in the CA2 after injection of Aβ1–40 into rats compared with control rats (Arevalo-Serrano et al., 2008). Additionally, Mahar and colleagues (2017) reported that in 1-month-old AD mice, there was decreased PV positive immunoreactivity in the CA1, CA2, and subiculum regions but no change in the DG. Two articles assessed PV positive cell density at multiple time points in an animal model. One article found that the CA1 region had increased PV positive cell density compared with WT controls at 15–17 weeks but had significantly decreased PV positive cell density at 23–25 weeks (Hijazi et al., 2019), whereas the other article found no changes in PV positive cell density in the DG and hilus of a mouse AD model at 12 months but at 18 months found a significant decrease (Loreth et al., 2012).

Table 3.

Summary of Parvalbumin Experiments in Identified Literature

	Year	Species	Sex	Assay type	Region	Finding
Rubio et al.	2012	Mouse	U	Immuno	H	Co-labeling shows accelerated loss of SHP inputs in J20 mice compared with controls
Villette et al.	2012	Rat	M	Immuno	CA1	No change in hippocampal amyloid deposits, or change in PV density 24 days after Aβ injection compared with controls
				Immuno	CA1	No change in hippocampal amyloid deposits, or change in PV/SOM density 24 days after Aβ injection compared with controls
				Tracer and Immuno	H-MS	No change in CB density in cells co-labeled PV positive/SOM +24 days after Aβ injection compared with controls
Yang et al.	2018	Mouse	M	Optogenetics in freely moving mice	EC/CA1	Selective degeneration of the ECIIPN-CA1PV pathway disables the excitatory and inhibitory synaptic balance in CA1-PN microcircuits and enhances CA1PN firing probability
Yang et al.	2018	Mouse	M	Optogenetics, MWM	EC/CA1	Optogenetic activation of ECIIPN in the AD mice via the TBS paradigm protects against the decay of the ECIIPN synaptic inputs into CA1PV and restores the excitatory and inhibitory synaptic balance in CA1PN microcircuits and restores behavior
Palop et al.	2007	Mouse	U	Immuno/Timm staining	DG	Timm-positive sprouting was specifically and heavily decorating somas and proximal dendrites of basket cells of PV co-labeled with NPY
Petrache et al.	2019	Mouse	M	Immuno	Dorsal LEC, CA1	Reduced PV positive cell density in dorsal LEC but not in CA1 or neocortex at 10–18 months. PV positive cells in dorsal LEC also had reduced GAD67
Petrache et al.	2019	Mouse	M	MWM	H	No difference in spatial learning discovered between hAPP mice with or without ErbB4 in PV neurons
Zhang et al.	2017	Mouse	U	MWM/Y-maze	H	Spatial memory retention impaired in Alzheimer's mouse homozygous for ErbB4
				MWM/Y-maze	H	Spatial memory retention recovered after deleting ErbB4 in PV neurons
				Western blot	H	No difference in proteolytic processing of hAPP before or after ErbB4 deletion in PV neurons
				Immuno/Thio-S	H	No difference in proteolytic processing of hAPP before or after ErbB4 deletion in PV neurons
				Immuno/Thio-S	H	No significant difference in plaque load between hAPP-J20/PV-Cre/ErbB4^+/+ and hAPP-J20/PV-Cre/ErbB4^f/f mice
				fEPSP	MPP/DG	LTP significantly depressed in H of hAPP-J20 compared with controls
				fEPSP	MPP/DG	LTP recovered after deleting ErbB4
				TBS	SC-CA1	Oligo-A-β42 suppressed LTP in CA1 area of PV-Cre/ErbB4^+/+ mice
				TBS	SC-CA1	Suppression effect of oligo-A-β42 was attenuated in PV-Cre/ErbB4^f/f mice
Mondragon-Rodriguez et al.	2018	Mouse	U	Whole cell	CA1→Sub	No difference in input/output relationship of eEPSCs or amplitude of type 1 events. Lower frequency of spontaneous EPSCs in PV cells of J20-TG mice
				Immuno	CA1/CA2/Sub	Barely any detectable levels of β-CTF expressed by PV positive interneurons. PV positive appears unaffected by β-CTF
				Whole cell	CA1/sub	Reduced maximum firing rate as well as slope of firing response (firing frequency vs. injected current) in PV cells from TG mice. Spike-frequency adaptation was found to be increased in TG mice. Non-TG mice responded to current stimulation by generating a larger number of APs than TG mice
				Immuno	Hi	1 Month: dramatically increased numbers of PV positive interneurons in Fs compared with Ms. Showed age-dependent decrease in PV positive hilar interneurons (most prevalent at 16 months). apoE isoform had no effect within Fs. Morphology: at 16 months, PV positive within hilus exhibited extensive processes stretching to molecular layer of H (nonexistent in Ms). PV positive number not correlated with learning ability
				Immuno	Hi	Age-dependent increase in PV positive hilar interneurons. PV positive number not correlated with learning ability. ApoE isoform had no effect in Ms. apoE-KI Ms showed sex-dependent decreased PV positive numbers at 12 months compared with apoE-KI Fs.^a
				Immuno	CA1	No effect observed other than F apoE3-KI>F apoE4-KI at 1 month of age.^b
				Immuno	CA3	No effect observed. SOM/NPY/PV
Leung et al.	2012	Mouse	F	Immuno	EC	No effect observed other than M apoE3-KI>M apoE4-KI PV positive numbers at 1 month. SOM/NPY/PV
			M	Immuno	CA1	Injections of Aβ resulted in reduction in PV positive cells in dorsal part of CA1 ipsilateral to injection site, compared with contralateral side and untreated controls
			MF	Immuno Immuno Immuno	CA2	Dorsal part of CA1 showed decreased PV positive cells compared with CA2. CA2 did not show significant reduction of PV positive cells compared with untreated controls or PBS-injected side (control)
					Hi	∼3% of neurons were PV positive. ∼3% of hAPP+ neurons expressed PV. 45–85% of PV positive neurons expressed hAPP
					CA1	No PV positive neurons present in the s.l.
Arevalo-Serrano et al.	2008	Rat	F	Immuno Immuno Optogenetic/Extracellular	CA1	∼3% of neurons were PV positive. 0.6% of hAPP+ neurons expressed PV. 55–100% of PV positive neurons expressed hAPP in the s.m.
Arevalo-Serrano et al.	2008	Rat	F	Immuno Immuno Optogenetic/Extracellular	CA1	∼16% of neurons were PV positive, which was significantly less than WT. 25% of hAPP+ neurons expressed PV. 80–90 PV positive neurons expressed hAPP in the s.o.
Hoefling et al.	2019	Mouse	F	Immuno Optogenetic/ExtracellularImmunoOptogenetic/ExtracellularOptogenetic	CA1	∼5% of neurons were PV positive. 4% of hAPP+ neurons expressed PV. 56–65% of PV positive neurons expressed hAPP in the s.r.
					H	hTau was accumulated only in CA1–3 pyramidal neurons of VLW, not WT or J20 mice. PV positive interneurons (VLW mice) accumulated pThr231 Tau but not hTau. Indicates that accumulation of mutated hTau in pyramidal neurons induces phosphorylation of endogenous Tau at residue Thr231 in PV positive interneurons in VLW mice
					HCA1	No accumulation of hTau
					HCA1CA1	Some PV positive interneurons in accumulated pThr231 and pThr205 Tau simultaneously
					HCA1CA1CA1	PV positive interneurons colocalized with both pSer262 Tau and pThr205 Tau
Davila-Bouziguet et al.	2019	Mouse	M	ImmunoOptogenetic/ExtracellularOptogeneticWhole cell	HCA1CA1CA1CA1	PV positive interneurons colocalized with both pSer262 Tau and pThr205 Tau
						Optogenetic activation of PV interneurons selectively restored hippocampal gamma oscillations impaired in AβO-injected mice, not theta oscillations
						Optogenetic activation of PV interneurons resynchronized CA1 PC spike phases relative to gamma oscillations
						Optogenetic activation of only ChR2-expressing PV interneurons increased the peak power of sIPSCs at gamma frequency. Peak frequency of sIPSCs was unchanged
						PV-evoked IPSCs significantly increased with each increased light intensity but not in controls. Paired-pulse depression only depressed for 40 Hz stimulation, not 5 Hz stimulation. Short-term depression only further depressed at 40 Hz stimulation. Controls showed depression at both frequencies. These depressions of sIPSC amplitudes was fully restored by optical stimulation
Chung et al.	2020	Mouse	U	Optogenetic/Whole cell	PV Interneurons	AβO-injection desynchronized PV interneuron spikes relative to gamma oscillations. Optogenetic activation of PV interneurons resynchronized SOM spike phases relative to gamma oscillations
				Optogenetic	H	Majority of eGFP-expressing inhibitory neurons were SST+, but only rarely PV positive.SOM/PV
				Immuno	CA1	PV-IR increased in APPPS1 mice versus controls
				Immuno	CA1/CA3	Increase in GAD67 and gephyrin immunoreactivities in PCL of both CA1 and CA3. Postsynaptic gephyrin clusters often colocalized with GAD67+ immunoreactivities, which probably represented presynaptic boutons on PV positive perisomatic projections (gephyrin, postsynaptic scaffold protein of GABA_a receptors and GAD67)
				ImmunoRNA extraction	CA1/CA3	Increased number of inhibitory synaptic clusters on PV positive projections onto the PCL of CA1 and CA3 of young APPPS1 H. Density of PV positive/VGAT+/gephyrin+ clusters was significantly higher in CA1 (∼70%) as well as in CA3 (∼35%) of the APPPS1 H in comparison to WT. CA3 had denser PV positive meshwork in PCL compared with CA1 (∼12% difference) (PV, gephyrin, presynaptic marker VGAT)
Schmid et al.	2016	Mouse	U	ImmunoRNA extraction	CA1/CA3	CA3 had higher PV positive somata than CA1 in both WT and APPPS1 mice, but APPPS1 had a trend to higher numbers. s.o.
Hollnagel et al.	2019	Mouse	M	ImmunoRNA extraction Whole cell patch-clamp	CA1/CA3	Overall PV-IR in stratum pyramidale (PCL) was significantly higher in APPPS1 mice—higher in CA3 compared with CA1. s.y.
					CA3	PV-IR increased in APPPS1 mice versus controls
					H	At 6 months, PV displayed no significant reduction in (what) mRNA expression compared with WT
					H	No significant differences in density of perisomatic inhibitory PV positive cells between APPxPS1 tg mice and WT
					CA1	APP/PS1 mice had increased sIPSC frequency, but amplitudes were not affected. sEPSC frequency or amplitudes showed no difference between APP/PS1 and WT controls
					CA1	sIPSC frequency was increased to WT levels 9–10 weeks after chronic (3 week) CNO treatment
Ramos et al.	2006	Mouse	M	Whole cell patch-clamp	CA1	Significant decrease in sIPSC frequency and amplitude in mCherry-expressing APP/PS1-PV-Cre mice 9–10 weeks after chronic (3 week) CNO treatment
Ramos et al.	2006	Mouse	M	Whole cell patch-clamp	CA1	23–25 Weeks—PV positive staining significantly decreased compared with WT
Hijazi et al.	2019	Mouse	M	Immuno	H	Observed early increase in excitability of PV interneurons at 15–17 weeks compared with WT-PV-Cre controls. Specifically, significantly depolarized resting membrane potential with unaltered input resistance, a significantly larger increase in AP firing frequency with increasing current injections, and significantly smaller AP half-width. PV interneurons were not affected at 7–9 weeks of age
				Whole cell patch-clamp	H	Both 15- to 17-week APP/PS1 and APP/PS1-PV-Cre mice had increased PV positive staining in CA1 compared with respective WT controls. No changes in total number of PV neurons
				Immuno	H	PV interneurons exposed to Aβ1–40 and Aβ1–42 showed increased excitability compared with PV cells exposed to a control peptide. Specifically, the input resistance of PV interneurons was increased. Resulted in increased AP firing
				Whole cell patch-clamp	H	Treatment with a BACE1 inhibitor (resulting in reduced Aβ levels), restored PV neuron properties to WT levels (decreased hyperexcitability)
				Whole cell patch-clamp	H	APP/PS1 mice showed spatial memory impairments at 15–17 weeks, coinciding with PV hyperexcitability at this age in this mouse model
				MWM	H	Decreasing activity of hyperexcitable PV interneurons during learning rescued spatial learning and memory in APP/PS1 mice. Chronic treatment of CNO combined with hM4Di-expressing APP/PS1 mice also showed significantly faster learning than mCherry-expressing mice. The effects were long-lasting as well—better learning 8 weeks after CNO injections
				MWM	H	Chronic (3 weeks) CNO-treatment at 16 weeks of APP/PS1-PV-Cre mice showed fully restored intrinsic PV properties compared with WT-PV-Cre mice. Rescued PV cell resting membrane potential, no effect on input resistance, significantly reduced AP firing frequency and AP half-width, all of which were altered in APP/PS1 mice. sIPSCs decreased to WT levels after CNO treatment
				Whole cell patch-clamp	H	Chemogenetic enhancement of PV activity in APP/PS1-PV-Cre mice at 23–25 weeks rescued learning and memory performance. Acute activation of PV neurons at week 24 has similar beneficial effects as prolonged inhibition of PV neurons at 16 weeks
				MWM	H	CNO-treated hM4Di-expressing APP/PS1-PV-Cre mice at 24 weeks of age showed 52% reduction in plaque numbers. Plaque size was unaffected. Also, soluble Aβ levels decreased compared with controls
				ELISA	CA1	PV positive/M2mAChR+ cells were found mainly in pyramidal cell layer and showed either multipolar or pyramidal-like somata. 28% of PV positive cells were M2mAChR+ as well
				Immuno	CA1	There is impairment in the EEG theta oscillations and coherent activity between the PFC and HPC CA1 and drastic impairments in theta–gamma oscillations PAC from week 2 onward, while PV positive interneurons count was not altered. Aka looks at what happens before PV neurons start to die
				Immuno+ephys	EC	Selective loss of SOM and NPY cells in the entorhinal cortex of PS1xAPP mice at 6 months of age, but not PV; however, extracellular APP was more toxic than intracellular as it lead to cytotoxic microglial activation
				Immuno	H	Reduction of the density of PV positive inhibitory neurons in the H of APP/PS1/CB1^−/− at 7 weeks of age
Gonzalez et al.	2008	Rat	F	Immuno	CA1–2	Reduction of PV neurons with age (∼40%) in 3 of 4 genetic models
Ahnaou et al.	2017	Mouse	MF	Immuno	DG	PV-IR neurons distributed within or close to the stratum granulare; no change in density from AD cases compared with controls in the -SG and hilus
Moreno-Gonzalez et al.	2009	Mouse	U	Immuno	CA1	No change in cell number
Aso et al.	2018	Mouse	U	Immuno	EC	No change in cell number
Verret et al.	2012	Mouse	MF	Immuno	H	Reduced Nav1.1. levels in PV cells, network hypersynchrony, primarily during reduced gamma oscillatory activity. Oscillatory rhythm is generated by inhibitory PV cells. Restoring Nav1.1 rescued phenotype
Verret et al.	2012	Human	MF	Immuno Cell attached epys	CA1	PV basket cells have selectively reduced spiking in AD model compared with WT
Waller et al.	2020	Human	MF	Immuno Cell attached epysImmuno	H	About 71.07% of PV-, or 82.12% of SST-positive interneurons showed pTau accumulation
Waller et al.	2020	Human	MF	Immuno Cell attached epysImmuno	H	Selective overexpression of hTau in PV- and SST-positive interneurons resulted in similar impairments of AHN: both reduced the number of BrdU- and DCX-labeled newborn cells and decreased the dendrite length, complexity, and spine density without changing the total number of ROV-GFP-labeled newborn neurons
Verret et al.	2012	Mouse	MF	Immuno	H	About 71.07% of PV-, or 82.12% of SST-positive interneurons showed pTau accumulation
Caccavano et al.	2020	Mouse	Both	Immuno	CA1	Reduction of PC cells in total CA1 as well as St Or and PCL
Zheng et al.	2020	Mouse	M	Immuno Immunoopto+whole cell ephys	CA1	AβO_1–42 causes synapse-specific dysfunction of PC-to-PV, but not PC-to-SST synapses
		Mouse	M	Immuno Immunoopto+whole cell ephys	CA1/2	Decrease in AD compared with WT in whole area, decrease in p.o., no change in s.o., no change in s.r.
		Human	MF	Immuno	CA3	No change in whole area or any subregions
Zallo et al.	2018	Mouse	M	Immuno	DG	No change in whole area or any subregions
Park et al.	2020	Mouse	U	Immuno	H	Decrease at (1 month) of age
Mahar et al.	2017	Mouse	M	ImmunoImmuno Immuno ImmunoImmuno	Sub	Decrease in AD compared with WT
					CA1/sub	Co-labeled with phospho tau, shows accumulation (qualitative)
					EC	Co-labeled with phospho tau, shows less accumulation than CA1 (qualitative)
					CA1/2	No change in cells/slice in whole area or any sub area
					CA3	No change in cells/slice in whole area or any sub area
Mondragon-Rodriguez et al.	2018	Mouse	M	ImmunoImmuno	DG	No change in cells/slice in whole area or any sub area
Mondragon-Rodriguez et al.	2018	Mouse	M	ImmunoImmuno	H	No change in cells/slice
Albuquerque et al.	2015	Mouse	M	ImmunoImmunoImmunoImmunoImmuno	Sub	No change in cells/slice
					CA1–3	No change
					CA1–3	No change
					DG	No change
					DG	Decrease
Loreth et al.	2012	Mouse	U	ImmunoImmunoImmuno Immuno	Hilus	No change
					Hilus	Decrease
					DG	50% of slices showed a decrease in PV in the GCL. All slices showed a decrease in the polymorphic layer
					CA1	Decrease compared with WT
					CA1	Colocalized with MC1 and PHF1 (early and late tauopathy markers)
					DG	No colocalization with MC1 and PHF1 (early and late tauopathy markers)
Popovic et al.	2008	Mouse	M	Immuno	DG	Cells were intensely immunoreactive for APP
Levenga et al.	2013	Mouse	U	Immuno Immuno	CA1	Co-labeled with ptau anti-PThr231 (AT-180). Soome, but not all, PARV-positive cells accumulated AT-180-positive P-Tau forms in soma and proximal dendrites
					CA1	AT-8 (1/500) and 12E8 (1/500) to recognize Tau protein phosphorylated in Ser202/Thr205 and Ser262/Ser356.No co-labeling therefore data indicated that PARV-positive hippocampal neurons in this mouse model specifically accumulate Tau phosphorylated in Thr231
					CA1	No loss of neurons
Wang et al.	2014	Mouse	MF	Immuno	CA3	Co-labeled with ptau anti-PThr231 (AT-180). Soome, but not all, PARV-positive cells accumulated AT-180-positive P-Tau forms in soma and proximal dendrites
Soler et al.	2017	Mouse	M	Immuno	CA3	AT-8 (1/500) and 12E8 (1/500) to recognize Tau protein phosphorylated in Ser202/Thr205 and Ser262/Ser356No co-labeling therefore data indicated that PARV-positive hippocampal neurons in this mouse model specifically accumulate Tau phosphorylated in Thr231
					CA3	BDA. The number of SH boutons per PARV-positive neuron was also diminished
					CA3	BDA. The number of SH boutons per PARV-positive neuron was also diminished, without change in innervation pattern
					DG	Co-labeled with ptau anti-PThr231 (AT-180). Some, but not all, PARV-positive cells accumulated AT-180-positive P-Tau forms in soma and proximal dendrites
					DG	AT-8 (1/500) and 12E8 (1/500) to recognize Tau protein phosphorylated in Ser202/Thr205 and Ser262/Ser356No co-labeling therefore data indicated that PARV-positive hippocampal neurons in this mouse model specifically accumulate Tau phosphorylated in Thr231
					DG	BDA tracer shows loss of SH innervations at 2 months of age
					H	Decrease compared with WT at 6–7 months
					H	At 14–19 months: decrease and decrease compared with 6–7 months
					CA1	Age- and phenotype-related differences were comparable to those observed in the CA3
					CA3	PV-IR increased in all the layers of CA3 region in 3-month-old transgenic versus the WT mice (fig. 8D–D′ vs. C–C′). The changes were even more apparent in 12-month-old animals, especially in basal dendrites of so layer and apical dendrites of sr layer (fig. 9D–D′ vs. C–C′)
Huh et al.	2016	Mouse	M	Immuno	DG	At 12 months of age, there was an increase in PV-IR compared with the control group, mainly in the dendritic projections of hilar and granular cells. A prominent increase of PV-IR was detected in the inner part of the stratum moleculare, where significant axonal staining was observed. But not at 3 months
Verdaguer et al.	2015	Mouse	M	Immuno

Overall: apoE4 has no effect on PV positive interneuron profiles.

Overall: ApoE4-mediated impairment of GABAergic interneurons in F apoE-KI mice occurs predominantly in the hilus.

AD, Alzheimer's disease; BDA, biotinylated dextran-amine; CB, cannabinoid; CTF, β-secretase-derived fragment; eEPSCs, evoked excitatory post synaptic current; CNO, nitric oxide; ELISA, enzyme-linked immunosorbent assay; GCL, granule cell layer; H-MS, hippocamposeptal; LEC, lateral entorhinal cortex; MF, male and female; NTG, non-transgenic; PARV, parvalbumin; PBS, phosphate-buffered saline; PC, parvalbumin cell; PCL, polymorphic cell layer; PV, parvalbumin; PV-IR, parvalbumin immunoreactivity; sEPSCs, spontaneous excitatory postsynaptic currents; SG, stratum granulare (granule cell layer); SHP, septohippocampal pathway; sIPSC, spontaneous inhibitory postsynaptic currents; s.m., stratum moleculare; s.l., stratum lacunosum; s.r., stratum radiatum; SST, somatostatin; TBS, theta burst stimulation; TG, transgenic; VLW, double-transgenic APP(SW)/Tau.

Five experiments were completed on human AD postmortem hippocampal tissue. Three experiments assessed PV positive cell density using immunohistochemistry, and all the three experiments found no change in PV positive cell density in the DG-SG and hilus (Takahashi et al., 2010) or the CA1 and entorhinal cortex (EC) (Waller et al., 2020). However, all the three experiments were limited to a small sample size (n = 10). Another experiment found that human AD postmortem tissue had decreased levels of a PV-specific voltage-gated sodium channel subunit, Nav1.1 (Verret et al., 2012). Finally, one article found increased pTau accumulation compared with controls (Zheng et al., 2020).

In animal AD models, the most commonly studied hippocampal region, CA1, had nine experiments that show decreased PV positive cell density (Ahnaou et al., 2017; Arevalo-Serrano et al., 2008; Hijazi et al., 2019; Hoefling et al., 2019; Levenga et al., 2013; Mahar et al., 2017; Soler et al., 2017; Takahashi et al., 2010; Zallo et al., 2018), two experiments that show an increase (Hijazi et al., 2019; Hollnagel et al., 2019), and four experiments that show no change compared with controls (Albuquerque et al., 2015; Loreth et al., 2012; Petrache et al., 2019; Villette et al., 2012).

In both the CA2 and CA3 regions of animal AD models, four experiments observed no change in PV positive cell density (Albuquerque et al., 2015; Arevalo-Serrano et al., 2008; Loreth et al., 2012; Mahar et al., 2017), whereas two experiments showed a decrease in the CA2 region compared with controls (Mahar et al., 2017; Takahashi et al., 2010).

In the whole DG, 12 experiments were performed across 9 articles. One experiment showed an increase in mossy inputs in an hAPP-J20 model (Palop et al., 2007). Six experiments concerned the amount of PV positive cells or PV immunoreactivity. Three experiments found no change in AD mice at 1 month (Mahar et al., 2017), 6 months (Albuquerque et al., 2015), and 12 months (Loreth et al., 2012); however, one experiment found decreased PV immunoreactivity at 18 months in AD mice compared with controls (Loreth et al., 2012), and one experiment found a decrease in PV positive cells at 12 months primarily in the dendritic projections of hilar and granular layer neurons. Additionally, one experiment found decreased PV immunoreactivity in 50% of brain slices at 14 months old in APPxPS1 mice compared with controls; however, the sample size was limited (n = 6). Three studies assessed tauopathy in PV interneurons. Levenga and colleagues (2013) found no colocalization with early and late tauopathy markers, Wang and colleagues (2014) found APP immunoreactivity in PV interneurons, and Soler and colleagues (2017) found that some PV positive cells co-labeled with a marker for tau phosphorylated at threonine 231.

Three experiments assessed the entorhinal cortex across four articles in AD animal models. Leung and colleagues (2012) found that male ApoE3 knock-in mice had more PV interneurons than male ApoE4 knock-in mice at 1 month old. Another experiment found no change in the number of PV positive cells in the EC at 6 months in an Aβ accumulation model (Moreno-Gonzalez et al., 2009). Concerning tauopathy, one experiment found slight pTau accumulation in the EC, but less than in the CA1 region, and Mondragon-Rodriguez and colleagues (2018) found slight pTau accumulation in the EC, but less than in CA1.

Two experiments across two articles looked at PV interneurons in the subiculum in animal AD models. Maher and colleagues (2017) found that there were less PV positive interneurons in the subiculum of mice in a tau AD model, and Albuquerque and colleagues (2015) found no change in 6-month-old mice of the same model.

Somatostatin

A total of 20 studies that analyzed the role of SOM interneurons in AD were identified. The distribution of species and sex studied is listed in Table 4. In total, we assessed 13 articles that used immunohistochemistry to assess SOM cell density in a total of 49 experiments in various regions and layers in the hippocampus. A total of 17 experiments exhibited decreased SOM immunoreactivity in AD humans and animal models compared with controls (Aguado-Llera et al., 2018; Albuquerque et al., 2015; Levenga et al., 2013; Moreno-Gonzalez et al., 2009; Ramos et al., 2006; Sekiguchi et al., 2009; Shi et al., 2020), whereas 17 experiments found no effect in the particular region studied (Albuquerque et al., 2015; Hoefling et al., 2019; Leung et al., 2012; Loreth et al., 2012; Palop et al., 2007; Villette et al., 2012; Waller et al., 2020).

Table 4.

Summary of Somatostatin Experiments in Identified Literature

	Year	Species	Sex	Assay type	Region	Finding
Villette et al.	2012	Rat	M	Tracer and Immuno	H-MS	Decreased CB/SOM density 24 days after Aβ injection but CB is upregulated in remaining CB/SOM cells
				Immuno	CA1	No change in NPY/SOM density 24 days after Aβ injection. No change in hippocampal amyloid deposits
				Immuno	CA1	No change in PV/SOM density 24 days after Aβ injection. No change in hippocampal amyloid deposits
				Tracer and Immuno	H-MS	No change in PV/SOM density 24 days after Aβ injection
				Immuno	CA1	No change in SOM density 24 days after Aβ injection. No change in hippocampal amyloid deposits
				Immuno	CA1	Selective decrease of CB/SOM density in stratum oriens by hippocampal Aβ
Palop et al.	2007	Mouse	U	Immuno	DG	Sprouting of SOM axons in molecular layer in 4- to 7-month-old hAPP-J20 mice compared with NTG
Palop et al.	2007	Mouse	U	Immuno	Hi	No change between NTG and 4- to 7-month-old hAPP-J20 mice
Leung et al.	2012	Mouse	F	Immuno	Hi	Increased SOM in female apoE3-KI compared with male at 1 month
			F	Immuno	Hi	Greater age-dependent reduction of SOM+ cells in apoE4-KI compared with apoE3-KI, correlated with spatial learning
			M	Immuno	Hi	No change between apoE isoforms. Age-dependent increase of SOM in apoE-KI mice, with no correlation with spatial learning
			M	Immuno	Hi	Increased SOM in male apoE4-KI compared with female from 12 to 16 months
			MF	Immuno	CA1	No effect observed other than increased SOM in apoE3-KI compared with apoE4-KI at 1 month
					CA3	No effect observed
					EC	No effect observed
Hoefling et al.	2019	Mouse	F	Immuno	Hi	30% of neurons were SOM+ in 3-month-old Tg2576 mice with no difference compared with WT. 30% of hAPP+ neurons expressed SOM. 50–60% of SOM+ neurons expressed hAPP.
					CA1	No SOM+ neurons present in 3-month-old Tg2576 mice with no difference compared with WT in the s.l.
					CA1	No SOM+ neurons present in 3-month-old Tg2576 mice with no difference compared with WT in the s.m.
					CA1	30% of neurons were SOM+ in 3-month-old Tg2576 mice. 30% of hAPP+ neurons expressed SOM. 75% of SOM+ neurons expressed hAPP in the s.o.
					CA1	10% of neurons were SOM+ in 3-month-old Tg2576 mice. 10% of hAPP+ neurons expressed SOM. 64% of SOM+ neurons expressed hAPP in the s.r.
Burgos-Ramos et al.	2007	Rat	M	SRIF Radioimmunoassay	H	Decreased SOM-like-IR due to 14 day i.c.v. Aβ25–35 infusion.Decreased function of SOM to inhibit adenylate cyclase
Burgos-Ramos et al.	2007	Rat	M	Adenylate cyclase (AC) assay	H	No effect on SOM inhibition of adenylate cyclase after single dose of Aβ25–35
Chung et al.	2020	Mouse	U	Optogenetic	CA1	Optogenetic activation resynchronized CA1 PC spike phases relative to theta oscillations only in AβO-injected mice
				Whole cell	CA1	Optogenetic activation increased the peak power of sIPSCs at theta frequency but not peak frequency AβO-injected mice
				Optogenetic/Whole cell	CA1	IPSCs significantly increased in AβO-injected mice with each increased light intensity compared with controls. Depressed paired-pulse and short-term depression for theta stimulation only. sIPSCs fully restored by optogenetic activation
				Optogenetic	CA1	AβO-injection desynchronized spikes relative to theta oscillations. This was restored by optogenetic activation
				Immuno	H	Majority of eGFP-expressing inhibitory neurons were SOM
Schmid et al.	2016	Mouse	U	RNA extraction	H	At 6 months, hippocampal neurons displayed significant reduction in SOM mRNA expression of PS1xAPP mice compared with WT
Ramos et al.	2006	Mouse	M	Immuno	CA1	Total volume of SOM axonal field decreased in SO in 6-month-old APPxPS1 mice
				RNA extraction	H	No reduction in SOM mRNA in 6-month-old APP mice compared with controls
				Immuno	H	Reduction in SOM+ cells and dystrophic SOM+ neurons in 6-month-old APPxPS1 mice compared with controls
				Immuno	CA1	Reduction in SOM+ and NeuN+ cells in SO in 6-month-old APPxPS1 mice
				RNA extraction	H	Reduction in SOM mRNA of APPxPS1 mice between 4- and 12-month-old APPxPS1 mice
				Western blot	H	Aβ load was inversely related to SOM mRNA expression in APPxPS1 mice at 6 months
				Immuno	CA1	SOM+/M2mAChR+ cells were located mainly along SO/alveus border and showed either multipolar or fusiform shape. 18.9% of SOM+ cells expressed M2mAChR
Gonzalez et al.	2008	Rat	F	Immuno	CA1	18.9% of SOM+ cells were M2mAChR+ as well after injection of Aβ1–40 peptide
Sekiguchi et al.	2009	Human	MF	ImmunoImmuno	CA4 (DG)	Significant loss of SOM+ neurons
					CA1	Significant loss of SOM+
					Subi	Significant loss of SOM+ neurons

Moreno-Gonzalez et al.	2009	Mouse	U	Immuno	EC	Selective loss of SOM and NPY cells in PS1xAPP mice at 6 months of age. Extracellular APP was more toxic than intracellular APP
Moreno-Gonzalez et al.	2009	Mouse	U	Immuno	EC	Cells that co-express SOM and NPY were significantly reduced in the PS1xAPP mice; however, extracellular APP was more toxic than intracellular APP
Waller et al.	2020	Human	MF	ImmunoImmuno	CA1	No change in cell number
Waller et al.	2020	Human	MF	ImmunoImmuno	SGZ/Hi	No change in cell number
Zheng et al.	2020	Mouse	M	Immuno	CA1SGZ/Hi	Selective overexpression of hTau in PV- and SST-positive interneurons resulted in similar impairments of AHN
					H	82.12% of SOM-positive interneurons showed pTau accumulation
					SGZ/HiCA1	82% of SOM+ interneurons showed pTau accumulation in AD transgenic mice compared with controls
		Human	MF	Immuno	CA1	Majority of pTau+ cells in SG and hilus co-labeled with GAD67, PV, or SOM
Park et al.	2020	Mouse	U	Optogenetic/Whole cell	CA1/2	No effect of AβO_1–42 on SOM-PC or PC-SOM synapses
Shi et al.	2020	Mouse	M	Immuno	CA1	Accumulation of Aβ and decreased cell density compared with WT seen at 9–18 months of age, not 1–3 or 4–6 months
Albuquerque et al.	2015	Mouse	M	Immuno	DG	No change in cells/slice in whole area or any subsections at 6 months in AD mice
					CA1	Overall decrease in whole area; decrease in s.o., no change in s.r.
					H	No change in cells/slice at 6 months in AD mice
					Sub	Decrease in cells/slice at 6 months in AD mice
					CA1/2	No change in cells/slice at 6 months in AD mice
					DG	Decrease in cells/slice at 6 months in AD mice
Loreth et al.	2012	Mouse	U	Immuno	CA1–3	No change in TauPS2APP mice at 12 or 18 months
					Hilus	No change in TauPS2APP mice at 12 or 18 months
					CA1	No change in TauPS2APP mice at 12 or 18 months
Levenga et al.	2013	Mouse	U	Immuno	CA1	Colocalized with early and late tauopathy markers in JNPL3(BL6) tg mice
					DG	Decreased in JNPL3(BL6) tg mice compared with WT
					DG	Decreased in JNPL3(BL6) tg mice compared with WT
					CA1	No colocalization with early and late tauopathy markers in JNPL3(BL6) tg mice
Soler et al.	2017	Mouse	M	Immuno	CA1	No colocalization detected between pTau and SOM in VLW mice
					DG	No colocalization detected between pTau and SOM in VLW mice
					CA3	No colocalization detected between pTau and SOM in VLW mice
Aguado-Llera et al.	2018	Rat	M	SRIF radioimmunoassay	CA1	SOM-like immunoreactivity is reduced in AD but rescued with IGF-1
				Immuno	H	SOM-like immunoreactivity is reduced in AD but rescued with IGF-2
				Western blot	H	SOM-like immunoreactivity is reduced in AD but rescued with IGF-1
				RT-PCR	H	SOM-like mRNA is reduced in AD but rescued with IGF-2

i.c.v., intracerebroventricular injection.

Six experiments studied SOM interneurons in postmortem human AD tissue. Five of these experiments used immunohistochemistry to quantify changes in SOM+ cell density in human AD tissue of Braak stage 4 or higher. Three experiments found a significant loss of SOM+ neurons in the CA1, DG, and subiculum (Sekiguchi et al., 2009), whereas two experiments found no change in SOM+ cell number in the CA1 and EC (Waller et al., 2020), compared with healthy controls postmortem. However, both these studies had small sample sizes of 6 (Sekiguchi, Habuchi, et al., 2009) and 10 (Waller et al., 2020). Finally, one experiment found increased pTau accumulation in SOM+ cells in postmortem human AD compared with controls (Zheng et al., 2020).

In studies that analyzed animal AD models, the majority of the experiments were in the CA1 region. Of these experiments, seven showed decreased SOM+ cells at time points between 6- and 18-months old in AD animals compared with controls (Aguado-Llera et al., 2018; Albuquerque et al., 2015; Levenga et al., 2013; Ramos et al., 2006; Shi et al., 2020; Villette et al., 2012), whereas two experiments showed no effect in AD animals compared with controls (Leung et al., 2012; Villette et al., 2012). Greater heterogeneity of results was found when assessing studies that analyzed other regions of the hippocampus. For example, four experiments assessed SOM immunoreactivity in the CA2 region of AD mice, two of which found decreased SOM immunoreactivity at 6 months (Albuquerque et al., 2015; Ramos et al., 2006), whereas two others observed no effect at various time points at 12 and 18 months, compared with controls; however, these two particular experiments assessed CA1–3 as a group and did not specifically assess CA2 separately (Loreth et al., 2012). Four experiments observed no change in SOM immunoreactivity in the CA3 region at 6, 12, and 18 months of AD animals compared with controls (Albuquerque et al., 2015; Leung et al., 2012; Loreth et al., 2012). One experiment found decreased SOM immunoreactivity in the CA1–3 regions (Ramos et al., 2006); however, the experiment did not specifically assess SOM+ levels in the CA3. In the hilus, four experiments found no change in SOM+ cell levels at various points between 3 and 18 months (Hoefling et al., 2019; Loreth et al., 2012; Palop et al., 2007), and one study found that only female apoE4-KI mice showed a decrease in SOM+ cell immunoreactivity compared with males and controls (Leung et al., 2012). In the subiculum, one article found no change in SOM immunoreactivity in a mouse AD model at 6 months compared with WT controls (Albuquerque et al., 2015). Two experiments assessed SOM+ levels in the EC, and one article found decreased levels in 4- to 7-month-old AD mice (Ramos et al., 2006), whereas the other found no effect at various points between 1- and 16-month-old apoE-knock-in mice compared with controls (Leung et al., 2012).

One article assessed SOM mRNA levels in APPxPS1 mice and found decreased levels starting at 4 months and onward. The same study found that APP mice had a nonsignificant reduction in SOM mRNA compared with WT controls (Ramos et al., 2006).

To assess the effect of tauopathy on SOM interneurons, 11 experiments that co-labeled SOM+ neurons with tauopathy markers in AD animal models were assessed. Five of these experiments demonstrated colocalization, or at least an increase in colocalization compared with controls (Levenga et al., 2013; Najm et al., 2020; Shi et al., 2020), two of which were specifically in the CA1 region (Levenga et al., 2013; Shi et al., 2020). Correspondingly, two experiments reported that this tau accumulation resulted in loss of SOM+ cells or SOM mRNA (Burgos-Ramos et al., 2007; Ramos et al., 2006). Four experiments found no colocalization in SOM+ interneurons in AD mice; one in the CA1 region (Soler et al., 2017), one in the CA3 region (Soler et al., 2017), and two in the DG (Levenga et al., 2013; Soler et al., 2017). Thus, the results demonstrate evidence that tauopathy does occur in SOM interneurons in AD (See also Supplementary Fig. S1).

We assessed one study evaluating the role of SOM interneurons in the genesis of hippocampal theta oscillations and found that they were impaired in three experiments for mice injected with soluble AβO at 28–49 days postnatal. However, these impairments were restored when optogenetically activated at theta frequency (Chunget al., 2020).

Finally, one article assessed the activity of SOM+ interneurons following chronic and acute doses of Aβ25–35 and found that there was a decrease of activity with a chronic 14 day infusion but no effect with a single dose of Aβ25–35 in male Wistar rats compared with controls (Burgos-Ramos et al., 2007).

Discussion

Cholecystokinin

Notably, few CCK studies were identified by this systematic review. In an APP^NL-F/NL-F model, Aβ accumulation was seen at 9–18 months of age and that degeneration that cannot be attributed to age occurs at 9–18 months but not in 1- to 3-month-old mice (Shi et al., 2020). Another study in an APP knock-in model found that 32% of CCK-positive interneurons in the CA1 subfield of the hippocampus contained APP buildup and that 95% of APP was found in CCK-positive interneurons (Rice et al., 2020). An amyloid injection model shows no change in amyloid cell deposits or CCK-positive cell numbers in the CA1 at either 5 or 24 days postinjection (Villette et al., 2012). These data, taken with the other articles found, suggest that CCK interneurons are a site of APP accumulation later in disease pathogenesis but are heavily impacted and require more study. Interestingly, CCK-positive interneurons are located where many type 1 cannabinoid (CB1) receptors are found, and so these cells may mediate the effects of THC, the psychoactive component of cannabis, and AD (Pelkey et al., 2017). Also given the fact that CCK-positive interneurons degenerate later in the disease progression, treatments targeting these cells may be helpful in cases of early-onset AD.

Neuropeptide Y

Most studies found a decrease in the number of NPY-positive interneurons in AD models compared with controls (Aguado-Llera and Canelles, 2018; Albuquerque et al., 2015; Ramos Baglietto-Vargas, et al., 2006; Loreth et al., 2012; Mahar et al., 2017). Mahar and colleagues (2017) found a decrease in the numbers of these cells in mice as young as 1 month old. Two models that did not see a change in the number of NPY neurons were the amyloid precursor protein intracellular domain model used by Ghosal and Pimplikar (2011) and the Aβ injection model used by Villette and colleagues (2012). Villette and colleagues (2012) used an acute injection model, with the latest time point studied being 24 days postinjection. Figure 2 shows that the number of NPY-positive cells in the hilus decreases in all studies but one. The study that showed an increase was due to an ApoE4 knock in (Leung et al., 2012). Together, the time courses and robust agreement of these studies suggest that NPY-positive interneurons are heavily impacted by AD, but that they may not be the first interneuron type impacted. There is a paucity of studies that assess the impact of AD-related NPY neuron degeneration and NPYs affect on adult neurogenesis in the DG, and so this is an area ripe for future study. A subset of NPY-positive interneurons, called neurogliaform cells (caveat: these cells also express other interneuron markers), would be a particularly interesting subtype to study. This is because neurogliaform cells have a significant number of en passant boutons. In these boutons, GABA is released into the extracellular space—not the synaptic cleft—to activate metabotropic GABA_A receptors and maintain a basal level of inhibition (Pelkey et al., 2017).

Parvalbumin

In every subsection of the hippocampal formation, there are conflicting results about whether the number of PV-positive interneuron is altered (Albuquerque et al., 2015; Aso et al., 2018; Loreth et al., 2012; Mahar et al., 2017; Petrache et al., 2019; Takahashi et al., 2010). There is evidence that AD affects inhibitory post-synaptic currents and gamma oscillations through PV interneurons and that inputs to PV interneurons in CA1 degenerate in AD (Chung et al., 2020; Park et al., 2020; Rubioet al., 2012).

In an hAPP-J20 mouse model, Palop and colleagues (2007) found aberrant innervation of PV interneurons by mossy fiber collaterals. Rice and colleagues (2020) found that in the stratum oriens of CA1, 41% of APP accumulation occurs in PV-positive interneurons. Villette and colleagues (2012) found that in their 24 day Aβ injection paradigm, a subset of PV/SOM interneurons was greatly affected by Aβ. Chung and colleagues (2020) also used an injection paradigm and found deficits in PV-positive interneurons that were rescued with optogenetic stimulation of PV interneurons. Increased PV-specific GABAergic input was found in 3-month-old APP/PS1 mice by Holnagel and colleagues (2019), whereas Hjazi and colleagues (2019) found an early increase in excitability in PV interneurons using whole-cell patch clamping in the same model. Verret and colleagues (2012) found a decrease in NaV.1 channels on PV interneurons.

In light of these findings, it would be pertinent for future research to assess PV interneurons as a potential early target for toxic APP products. This could lead to a loss of lateral inhibition, which could cause first early excitability and later, death, via toxic APP buildup and excitotoxicity. Further studies could be carried out to delineate if the decrease in NaV.1 levels found by Verret and colleagues (2012) is the cell's attempt to control aberrant activity, or a target of APP toxicity through affects on gephyrin. Interestingly, the articles that found no change in PV interneuron numbers were also models of tau and not APP accumulation. This agrees with findings that PV interneurons are affected early, and not late in AD. It would also be interesting for future studies to assess SOM and PV concurrently to see if the finding can be corroborated that the cell type that expresses both SOM and PV suffer more acutely. PV-positive cells in the DG are thought to participate in neurogenesis by controlling the integration of adult-born granule cells (abGCs) into the circuit; abGCs that do not receive inputs form PV-positive cells are much more likely to die (Song et al., 2013). As adult neurogenesis is a possible mechanism of memory, targeting these cells early in disease could be beneficial. Indeed, one group found that increasing the excitability of PV interneurons in early Alzheimer's in a mouse APP/PS1 model was beneficial (Hijazi et al., 2019).

Somatostatin

SOM-positive interneurons showed both APP and tau accumulation, although Rice and colleagues (2020) found minimal APP accumulation (Hoefling et al., 2019; Shi et al., 2020). There is disagreement as to whether the number of SOM-positive interneurons is lost or not; Albuquerque and colleagues (2015) found a decrease in the number of PV-positive cells in 6-month-old mice in the CA1/2 region and the stratum radium of CA3, whereas Loreth and colleagues (2012) found no change in the pooled CA1–3 regions, the DG, or the hilus in 12- or 18-month-old mice, although both articles used a tau accumulation model (Albuquerque et al., 2015; Sekiguchi et al., 2009). Similar phosphotau accumulation was found by Zheng and colleagues (2020) finding a robust accumulation in two separate mouse models, as well as human tissue, whereas Soler and colleagues (2017) found no co-labeling in any hippocampal subfield of tau phosphorylated at threonine 231. Villette and colleagues (2012) found no change in hippocampal amyloid deposits or in the number of SOM-positive interneurons after acute Aβ injections. Theta oscillations were shown to be affected by SOM-positive interneuron loss, and this phenomenon was confirmed with an optogenetic rescue experiment (Chung et al., 2020). SOM interneurons are integral in the production of theta oscillations and have more recently been implicated in lateral inhibition to maintain the fidelity of neuronal signals during memory retrieval (Stefanelli et al., 2016). The heterogeneity of findings about whether the number of SOM-positive interneurons increases, decreases, or remains unaffected suggests that more studies in this area should be performed and also that SOM-positive interneurons may themselves be heterogeneous and should be studied in conjunction with other intraneuronal markers. There is emerging evidence that the SST14 neuropeptide acts to exacerbate Aβ aggregation, and so the heterogeneity of results could be due to the time it takes for this event to happen in different AD models (Solarski et al., 2018). SOM-positive interneuron degeneration in the hilus has previously been shown to be implicated in nonpathological age-related memory changes, and further treatments with a low dose of the antiepileptic drug levetiracetam were able to upregulate SOM expression (Spiegel et al., 2013). It is important to note that SOM is a peptide hormone that binds to a host of G-protein-coupled receptors in the brain and so changes in the level of this peptide hormone as well as loss of GABA signaling by interneurons positive for this marker must be considered in future studies (Pelkey et al., 2017).

Conclusions

This systematic review found that there is strong evidence that PV interneurons are affected early in the disease by toxic Aβ fragments. This leads to a loss of lateral inhibition and increased excitotoxicity. The loss of lateral inhibition will likewise affect SOM interneurons indirectly while the SOM neuropeptide may act to slowly worsen toxic Aβ fragment accumulation. The literature suggests that NPY- and CCK-positive interneurons are affected later in the progression of the disease and lead to loss of regulation of adult neurogenesis and the cannabinoid system, respectively. In the future, treatments for AD may fall into two categories: treatment for those who are diagnosed early and those who are diagnosed only when symptomatic. Treatments that upregulate PV and SOM activity may buy patients some time before lateral inhibition breaks down and memory fidelity is lost. Treatments that target CCK- and NPY-positive interneurons may be helpful in the late disease where the SOM and PV interneurons have already degraded. There is also a possibility that targeting CCK interneurons may increase overall inhibition through the CB1 pathway, by disinhibiting GABA release. This systematic review aims to identify gaps in the literature and opportunities for new experiments to strengthen our understanding in the field.

Footnotes

Authors' Contributions

H.M.O.R. and N.C.-M. were responsible for the conceptualization, reference selection, and writing of this article. T.S. was responsible for checking the applicability of each included reference, as well as editing the text and designing some figures. B.R.C. was responsible for conceptualization, writing of the article, and editing of the article.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by a CIHR catalyst grant (FRN:163015).

Supplementary Material

Supplementary Figure S1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

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