TY - JOUR T1 - p110δ PI 3-kinase inhibition perturbs APP and TNFα trafficking, reduces plaque burden, dampens neuroinflammation and prevents cognitive decline in an Alzheimer's disease mouse model JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.0674-19.2019 SP - 0674-19 AU - Ramón Martínez-Mármol AU - Nika Mohannak AU - Lei Qian AU - Tong Wang AU - Rachel S. Gormal AU - Marc J. Ruitenberg AU - Bart Vanhaesebroeck AU - Elizabeth J. Coulson AU - Frédéric A. Meunier Y1 - 2019/07/30 UR - http://www.jneurosci.org/content/early/2019/07/29/JNEUROSCI.0674-19.2019.abstract N2 - Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptide. Accumulation of Aβ, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. 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 (TNFα) by microglial cells in the familial AD APPswe/PS1ΔE9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3Kδ (δD910A) had reduced Aβ peptides levels and plaques in the brain and an abrogated inflammatory response compared to APP/PS1 littermates. 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. Importantly, APP/PS1/δD910A mice exhibited no spatial learning or memory deficits. 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.SIGNIFICANCE STATEMENTDuring Alzheimer's disease, the accumulation of the toxic Aβ peptide in plaques is associated with a chronic excessive inflammatory response. Uncovering new drug targets that simultaneously reduce both Aβ plaque load and neuroinflammation holds therapeutic promises. Using a combination of genetic and pharmacological approaches, we found that the p110δ isoform of PI 3-kinase (PI3Kδ) is involved in anterograde trafficking of the amyloid precursor protein (APP) in neurons, and in the secretion of TNFα from microglial cells. Genetic inactivation of PI3Kδ reduces Aβ plaque deposition and abrogates the inflammatory response, resulting in a complete rescue of the life span and spatial memory performance. We conclude that inhibiting PI3Kδ represents a novel therapeutic approach to ameliorate AD pathology, by dampening plaque accumulation and microglial-dependent neuroinflammation. ER -