![]() Uncovering new drug targets that simultaneously reduce both Aβ plaque load and neuroinflammation holds therapeutic promise. SIGNIFICANCE STATEMENT During Alzheimer's disease (AD), the accumulation of the toxic amyloid-β (Aβ) peptide in plaques is associated with a chronic excessive inflammatory response. Our data highlight inhibition of PI3Kδ as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing. Importantly, APP/PS1/δ D910A mice exhibited no spatial learning or memory deficits. Mechanistic investigations reveal that PI3Kδ inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted Aβ peptide. Moreover, APP/PS1 mice with kinase-inactive PI3Kδ (δ D910A) had reduced Aβ peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Here, we report that inactivation of the p110δ isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor-alpha by microglial cells in the familial AD APP swe/PS1 ΔE9 (APP/PS1) mouse model. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Accumulation of Aβ, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptide.
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