Journal
JOURNAL OF NEUROSCIENCE
Volume 39, Issue 40, Pages 7976-7991Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0674-19.2019
Keywords
Alzheimer's disease; amyloid precursor protein; axon trafficking; neuroinflammation; p110delta; TNF-alpha
Categories
Funding
- National Health and Medical Research Council (NHMRC) [1049236, 1005964, 1060538]
- Biotechnology and, Biological Sciences Research Council [BB/I007806/1]
- Cancer Research UK [C23338/A25722]
- National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre
- NHMRC Senior Research Fellowship [569596]
- Clem and Jones Foundation
- State Government of Queensland
- NHMRC Boosting Dementia Research Initiative
- Discovery Early Career Researcher Fellowship [DE170100546]
- SpinalCure Australia Career Development Fellowship
- Australian Research Council [DE170100546] Funding Source: Australian Research Council
- National Health and Medical Research Council of Australia [1060538] Funding Source: NHMRC
- BBSRC [BB/I007806/1] Funding Source: UKRI
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Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-beta (A beta) peptide. Accumulation of A beta, 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 delta 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(Delta E9) (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3K delta (delta(D910A)) had reduced A beta peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3K delta 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 beta peptide. Importantly, APP/PS1/delta(D910A) mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3K delta 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.
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