Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms.
ApoE
LDLR
OPC
metabolism
microglia
myelin
tau
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
04 08 2021
04 08 2021
Historique:
received:
26
03
2021
revised:
03
05
2021
accepted:
27
05
2021
pubmed:
23
6
2021
medline:
14
8
2021
entrez:
22
6
2021
Statut:
ppublish
Résumé
APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.
Identifiants
pubmed: 34157306
pii: S0896-6273(21)00413-X
doi: 10.1016/j.neuron.2021.05.034
pmc: PMC8349883
mid: NIHMS1712133
pii:
doi:
Substances chimiques
Apolipoproteins E
0
Receptors, LDL
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2413-2426.e7Subventions
Organisme : NINDS NIH HHS
ID : R01 NS090934
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS090934
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG047644
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG047644
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS118146
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests D.M.H. and C.I. are listed as inventors on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. C2N Diagnostics has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M.H. is on the scientific advisory board of Denali and consults for Genentech, Merck, and Cajal Neurosciences.
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