Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model.
Alzheimer Disease
/ metabolism
Animals
Blood-Brain Barrier
/ metabolism
Brain
/ metabolism
CD11b Antigen
/ metabolism
CD18 Antigens
/ metabolism
Cognitive Dysfunction
/ metabolism
Dendritic Spines
/ metabolism
Disease Models, Animal
Fibrinogen
/ metabolism
Humans
Imaging, Three-Dimensional
Mice
Microglia
/ metabolism
Plaque, Amyloid
/ metabolism
Reactive Oxygen Species
/ metabolism
blood-brain barrier
coagulation
complement
dementia
dendritic spines
fibrin
iDISCO
innate immunity
multiple sclerosis
neurovascular
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
20 03 2019
20 03 2019
Historique:
received:
17
04
2018
revised:
21
09
2018
accepted:
04
01
2019
pubmed:
10
2
2019
medline:
5
11
2019
entrez:
10
2
2019
Statut:
ppublish
Résumé
Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.
Identifiants
pubmed: 30737131
pii: S0896-6273(19)30015-7
doi: 10.1016/j.neuron.2019.01.014
pmc: PMC6602536
mid: NIHMS1519493
pii:
doi:
Substances chimiques
CD11b Antigen
0
CD18 Antigens
0
Reactive Oxygen Species
0
Fibrinogen
9001-32-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
1099-1108.e6Subventions
Organisme : NIA NIH HHS
ID : P50 AG023501
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103412
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS082976
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007334
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097976
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG019724
Pays : United States
Organisme : NINDS NIH HHS
ID : F32 NS096920
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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