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 (Ab) fragments; SOM interneurons are affected indirectly while the SOM neuropeptide may act to slowly worsen toxic Ab 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.

Alzheimer’s Disease Enhanced Tonic Inhibition is Correlated With Upregulated Astrocyte GABA Transporter-3/4 in a Knock-In APP Mouse Model

“…ADassociated hyperexcitability is thought to spread the disease pathology between brain subregions (Khan et al, 2014;Petrache et al, 2019). The process by which this develops remains to be fully answered, with one hypothesis referring to the selective aberrant behaviour of inhibitory neurotransmitter GABA-containing interneurons (Rice et al, 2020;Shi et al, 2020;Xu et al, 2020;Reid et al, 2021), despite an elevated background inhibition observed in AD by others (Jo et al, 2014;Wu et al, 2014). Surprisingly, the levels of astrocyte glutamate decarboxylase 67 (GAD67), an enzyme that converts glutamate to GABA, is shown to be elevated in astrocytes in AD patients and mouse models of AD (Wu et al, 2014).…”

The Engram’s Dark Horse: How Interneurons Regulate State-Dependent Memory Processing and Plasticity

“…Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and one of the most common causes of dementia. Although the underlying mechanisms of AD are still not completely understood, disrupted interneuron function has been associated with AD ( Reid et al, 2021 ). For example, accumulation of the amyloid-β (Aβ) protein, which is a classical hallmark of AD pathology, has been shown to alter excitatory/inhibitory balance; this aspect of disease pathology is implicated in the observed learning and memory deficits associated with AD ( Verret et al, 2012 ; Palop and Mucke, 2016 ; Hijazi et al, 2020 ).…”

“…For example, accumulation of the amyloid-β (Aβ) protein, which is a classical hallmark of AD pathology, has been shown to alter excitatory/inhibitory balance; this aspect of disease pathology is implicated in the observed learning and memory deficits associated with AD ( Verret et al, 2012 ; Palop and Mucke, 2016 ; Hijazi et al, 2020 ). Recent work in AD mouse models has found either decreased, unchanged, or increased PV+ cell density in CA1 ( Hollnagel et al, 2019 ; Reid et al, 2021 ). The differences in findings are likely explained in part by differences between various transgenic AD mouse models and the age at which mice are examined in different studies ( Ruden et al, 2021 ).…”

“…The differences in findings are likely explained in part by differences between various transgenic AD mouse models and the age at which mice are examined in different studies ( Ruden et al, 2021 ). Recent studies have more consistently found reductions in DG PV+ expression in older AD transgenic animals compared to their wild-type counterparts ( Loreth et al, 2012 ; Reid et al, 2021 ). SST+ interneurons’ immunoreactivity is also altered in both AD humans and animal models.…”

“…SST+ interneurons’ immunoreactivity is also altered in both AD humans and animal models. For example, multiple studies, in both animal models and human post-mortem brains, found decreased somatostatin expression in CA1, but no clear change in CA3 or DG ( Reid et al, 2021 ). Somatostatin expression is also reduced in the human neocortex in early AD ( Guennewig et al, 2021 ).…”