Neuronal subtype governs amyloid structure, cellular response, and cognitive outcome in genetically targeted APP mouse models.

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00919-9.