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.
Alzheimer Disease
/ genetics
Amyloid beta-Protein Precursor
/ metabolism
Animals
Axonal Transport
/ genetics
Class I Phosphatidylinositol 3-Kinases
/ genetics
Cognitive Dysfunction
/ genetics
Cytokines
/ metabolism
Encephalitis
/ genetics
Female
Male
Maze Learning
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons
/ metabolism
Plaque, Amyloid
/ genetics
Point Mutation
Primary Cell Culture
Spatial Memory
Tumor Necrosis Factor-alpha
/ metabolism
Alzheimer's disease
TNF-alpha
amyloid precursor protein
axon trafficking
neuroinflammation
p110delta
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
02 10 2019
02 10 2019
Historique:
received:
25
03
2019
revised:
26
06
2019
accepted:
22
07
2019
pubmed:
1
8
2019
medline:
3
7
2020
entrez:
1
8
2019
Statut:
ppublish
Résumé
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 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 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 by microglial cells in the familial AD APP
Identifiants
pubmed: 31363064
pii: JNEUROSCI.0674-19.2019
doi: 10.1523/JNEUROSCI.0674-19.2019
pmc: PMC6774409
doi:
Substances chimiques
Amyloid beta-Protein Precursor
0
Cytokines
0
Tumor Necrosis Factor-alpha
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Pik3cd protein, mouse
EC 2.7.1.137
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7976-7991Subventions
Organisme : Cancer Research UK
ID : 25722
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C23338/A25722
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/I007806/1
Pays : United Kingdom
Informations de copyright
Copyright © 2019 the authors.
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