p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model

Abstract

Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-␤ (A␤) peptide. Accumulation of A␤, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being 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 p110␦ 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 ⌬E9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3K␦ (␦ D910A) had reduced A␤ peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3K␦ inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted A␤ peptide. Importantly, APP/PS1/␦ D910A mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3K␦ 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.

Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice

“…WT = wild type C57BL/6 cognitive decline [26]. Furthermore, elevated systemic TNF-α produces acute cognitive dysfunction and inhibition TNF-α trafficking prevents cognitive decline in an Alzheimer's disease mouse model [27]. Our previous study also demonstrated that MV-induced neuroinflammation affected postoperative memory dysfunction and TLR4 knockout ameliorates neuroinflammation.…”

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches

“…Although essentially unable to cross the blood-brain barrier [ 36 ], this inhibitor nevertheless exhibited in vitro outcomes consistent with the ability, should it be administered perispinally to ensure it reaches the brain [ 3 ] in order to reduce TNF and thus neuroinflammation in a mouse model of AD. As might be expected, genetically inactivating this kinase produced the same TNF and neuroinflammation outcomes in vivo as the inhibitor did in vitro , as well as reducing cognitive decline [ 37 ]. Notably, a range of other anti- or proinflammatory cytokines were unaffected.…”

“…Studies on the roles of the delta family of phosphoinosositide 3-kinases (PI3Ks) of cytokine signaling pathways independently demonstrate the centrality of TNF in models of stroke [ 36 ] and AD [ 37 ], the most common members of the rapid and slow onset groups respectively. This has been achieved in a stroke model by inhibiting one of this family of kinases, which reduced TNF trafficking and secretion of lipopolysaccharide-induced TNF in macrophages [ 38 ].…”

PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors in aging

“…Similar to observations in gliomas, dysregulation of PAM-dependent mechanisms is observed in age-related neurodegenerative conditions, suggesting their contributions to CNS disease progression in aging. Indeed, PAM induction of aberrant cell cycle progression, impaired autophagy and neuroinflammation is implicated in AD pathogenesis [ 136 – 138 ]. Additionally, data suggest that patients displaying AD symptomology maintain poorer cancer-related outcomes, including diagnosis with more advanced stages of cancer, decreased life expectancies and increased mortality rates [ 139 – 143 ].…”