| First Author | Martínez-Mármol R | Year | 2019 |
| Journal | J Neurosci | Volume | 39 |
| Issue | 40 | Pages | 7976-7991 |
| PubMed ID | 31363064 | Mgi Jnum | J:287771 |
| Mgi Id | MGI:6363274 | Doi | 10.1523/JNEUROSCI.0674-19.2019 |
| Citation | Martinez-Marmol R, et al. (2019) p110delta PI3-Kinase Inhibition Perturbs APP and TNFalpha Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model. J Neurosci 39(40):7976-7991 |
| abstractText | Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-beta (Abeta) peptide. Accumulation of Abeta, 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 p110delta 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 APPswe/PS1DeltaE9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3Kdelta (delta(D910A)) had reduced Abeta peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3Kdelta inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted Abeta peptide. Importantly, APP/PS1/delta(D910A) mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3Kdelta 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 STATEMENT During Alzheimer's disease (AD), the accumulation of the toxic amyloid-beta (Abeta) peptide in plaques is associated with a chronic excessive inflammatory response. Uncovering new drug targets that simultaneously reduce both Abeta plaque load and neuroinflammation holds therapeutic promise. Using a combination of genetic and pharmacological approaches, we found that the p110delta isoform of phosphoinositide 3-kinase (PI3K) is involved in anterograde trafficking of the amyloid precursor protein in neurons and in the secretion of tumor necrosis factor-alpha from microglial cells. Genetic inactivation of PI3Kdelta reduces Abeta plaque deposition and abrogates the inflammatory response, resulting in a complete rescue of the life span and spatial memory performance. We conclude that inhibiting PI3Kdelta represents a novel therapeutic approach to ameliorate AD pathology by dampening plaque accumulation and microglial-dependent neuroinflammation. |
