Publication Date

1-6-2026

Journal

Molecular Neurodegeneration

DOI

10.1186/s13024-025-00919-9

PMID

41495836

PMCID

PMC12790121

PubMedCentral® Posted Date

1-6-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Pathological heterogeneity is increasingly appreciated in Alzheimer’s disease, yet we do not know how distinct aggregate conformations arise or influence cognitive outcomes. In an amyloid mouse model, we found that different brain regions formed structurally distinct Aβ deposits, prompting us to test whether neuronal subtypes shape aggregate conformation. To address this, we created transgenic mice expressing the same APP construct in either glutamatergic or GABAergic neurons. APP expression in GABAergic neurons resulted in diffuse plaques with high Aβ42/Aβ40 ratios and minimal gliosis, while glutamatergic expression produced neuritic plaques with activated glia. Despite similar Aβ levels, only mice with neuritic plaques exhibited cognitive deficits. These results show that the neuronal source of APP shapes Aβ plaque structure, influencing both cellular response and behavioral outcome. Our findings affirm that amyloid conformation and gliosis—rather than total Aβ load—drive disease progression, and suggest that regional differences in neuronal composition may govern vulnerability.

Keywords

Neuronal subtype, GABAergic, APP, Amyloid plaque, Transgenic mouse, Heterogeneity

Published Open-Access

yes

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