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p110 delta PI3-Kinase Inhibition Perturbs APP and TNF alpha Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model | |
2019 | |
发表期刊 | JOURNAL OF NEUROSCIENCE |
ISSN | 0270-6474 |
EISSN | 1529-2401 |
卷号 | 39期号:40页码:7976-7991 |
发表状态 | 已发表 |
DOI | 10.1523/JNEUROSCI.0674-19.2019 |
摘要 | 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. |
关键词 | Alzheimer's disease amyloid precursor protein axon trafficking neuroinflammation p110delta TNF-alpha |
URL | 查看原文 |
收录类别 | SCI |
WOS研究方向 | Neurosciences & Neurology |
WOS类目 | Neurosciences |
WOS记录号 | WOS:000488506700015 |
WOS关键词 | TUMOR-NECROSIS-FACTOR ; AMYLOID PRECURSOR PROTEIN ; B-CELL ; BETA ; CLEARANCE ; MICROGLIA ; MICE ; PI3K ; INFLAMMATION ; PATHOGENESIS |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/120186 |
专题 | 个人在本单位外知识产出 |
通讯作者 | Coulson, Elizabeth J.; Meunier, Frederic A. |
作者单位 | 1.Univ Queensland, Clew Jones Ctr Ageing Dementia Res, Queensland Brain Inst, Brisbane, Qld 4072, Australia 2.Univ Queensland, Fac Med, Sch Biomed Sci, Brisbane, Qld 4072, Australia 3.UCL, Canc Inst, Cell Signalling, London WC1E 6DD, England |
推荐引用方式 GB/T 7714 | Martinez-Marmol, Ramon,Mohannak, Nika,Qian, Lei,et al. p110 delta PI3-Kinase Inhibition Perturbs APP and TNF alpha Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model[J]. JOURNAL OF NEUROSCIENCE,2019,39(40):7976-7991. |
APA | Martinez-Marmol, Ramon.,Mohannak, Nika.,Qian, Lei.,Wang, Tong.,Gormal, Rachel S..,...&Meunier, Frederic A..(2019).p110 delta PI3-Kinase Inhibition Perturbs APP and TNF alpha Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model.JOURNAL OF NEUROSCIENCE,39(40),7976-7991. |
MLA | Martinez-Marmol, Ramon,et al."p110 delta PI3-Kinase Inhibition Perturbs APP and TNF alpha Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model".JOURNAL OF NEUROSCIENCE 39.40(2019):7976-7991. |
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