Seed‐induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by severe neuronal loss as well as the accumulation of amyloid‐β (Aβ), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aβ can be initiated by prion‐like seeding, the impact and functional consequences of induced Aβ deposits (Aβ seeding) on neurons still remain open questions. Here, we find that Aβ seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two APP transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Aβ deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Aβ seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Aβ seeding and the consequences thereof and attributes microglia an important role in diminishing Aβ seeding by environmental enrichment. Synopsis Prion‐like Aβ seeding impairs neurogenesis and enhances cell death leading to electrophysiological abnormalities and memory deficits. Environmental stimuli reverse this memory impairment and diminish Aβ seeding by activating phagocytic microglia. Seed‐induced Aβ deposits directly affect adult neurogenesis and induces cell death leading to impaired memory. Housing the mice in an environmental enrichment potently reverses neurogenic and memory deficits. Activated phagocytic microglia prevent Aβ seeding under enriched environmental condition. Graphical Abstract Environmental stimuli and voluntary exercise, known to ameliorate dementia rescue adult neurogenesis in transgenic mouse models by activating phagocytic microglia to reduce amyloid‐β seeding.