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Excitatory and inhibitory neurons accumulate distinct Ab plaques in mouse models of APP overexpression

ABSTRACT: Amyloid plaque heterogeneity is a hallmark of Alzheimer's disease (AD), yet the mechanisms governing plaque diversity and its relationship to disease progression remain poorly understood. Although both diffuse and neuritic plaques are present in AD brain tissue, we do not know how these distinct conformations arise or influence pathological outcomes. Here, we developed transgenic mouse models expressing identical APP constructs in either glutamatergic or GABAergic neurons to investigate how cellular context shapes amyloid pathology. This approach revealed that the cellular source of APP influences both the biochemical composition and structural characteristics of resulting Aβ deposits. APP expressed in GABAergic neurons generated exclusively diffuse plaques with elevated Aβ42/Aβ40 ratios that failed to induce gliosis, while glutamatergic expression produced primarily neuritic plaques surrounded by activated microglia. Differences in deposit characteristics appeared to arise from fundamental variations in APP processing between excitatory and inhibitory neurons. Moreover, only neuritic plaques generated by glutamatergic neurons caused behavioral deficits, while diffuse plaques from GABAergic neurons did not impair cognition despite substantial amyloid burden. These findings may provide new insight into the mechanisms underlying amyloid heterogeneity in AD and suggest that plaque conformation, rather than simply amyloid load, may influence cognitive trajectories. snRNA-seq revealed that microglia from the excitatory models showed many DAM genes were upregulated, which were absent in the inhibitory model. The data also revealed there were no changes in expression of key APP processing enzymes between excitatory or inhibitory neurons in each model.

ORGANISM(S): Mus musculus

PROVIDER: GSE292822 | GEO | 2026/01/07

REPOSITORIES: GEO

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Project description:A hallmark pathology of Alzheimer’s disease (AD) is the formation of amyloid ß (Aß) deposits that exhibit diverse localization and morphologies, ranging from diffuse to cored-neuritic deposits in brain parenchyma, with cerebral vascular deposition in leptomeningeal and parenchymal compartments. Most AD brains exhibit the full spectrum of pathologic Aß morphologies. In the course of studies to model AD amyloidosis, we have generated multiple transgenic mouse models that vary in the nature of the transgene constructs that are expressed; including the species origin of Aß peptides, the levels and length of Aß that is deposited, and whether mutant presenilin 1 (PS1) is co-expressed. These models recapitulate features of human AD amyloidosis, but interestingly some models can produce pathology in which one type of Aß morphology dominates. In prior studies of mice that primarily develop cored-neuritic deposits, we determined that Aß deposition is associated with changes in cytosolic protein solubility in which a subset of proteins become detergent-insoluble, indicative of secondary proteome instability. Here, we survey changes in cytosolic protein solubility across seven different transgenic mouse models that exhibit a range of Aß deposit morphologies. We find a surprisingly diverse range of changes in proteome solubility across these models. Mice that deposit human Aß40 and Aß42 in cored-neuritic plaques had the most robust changes in proteome solubility. Insoluble cytosolic proteins were also detected in the brains of mice that develop diffuse Aß42 deposits but to a lesser extent. Notably, mice with cored deposits containing only Aß42 had relatively few proteins that became detergent-insoluble. Our data provide new insight into the diversity of biological effects that can be attributed to different types of Aß pathology and support the view that fibrillar cored-neuritic plaque pathology is the more disruptive Aß pathology in the Alzheimer’s cascade.

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Excitatory and inhibitory neurons accumulate distinct Ab plaques in mouse models of APP overexpression

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