Kalirin-7 prevents dendritic spine dysgenesis induced by amyloid beta-derived oligomers.
Alzheimer's disease
Rac1
guanine-nucleotide exchange factors
synapse
Journal
The European journal of neuroscience
ISSN: 1460-9568
Titre abrégé: Eur J Neurosci
Pays: France
ID NLM: 8918110
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
25
09
2018
revised:
19
11
2018
accepted:
13
12
2018
pubmed:
20
12
2018
medline:
15
7
2020
entrez:
20
12
2018
Statut:
ppublish
Résumé
Synapse degeneration and dendritic spine dysgenesis are believed to be crucial early steps in Alzheimer's disease (AD), and correlate with cognitive deficits in AD patients. Soluble amyloid beta (Aβ)-derived oligomers, also termed Aβ-derived diffusible ligands (ADDLs), accumulate in the brain of AD patients and play a crucial role in AD pathogenesis. ADDLs bind to mature hippocampal neurons, induce structural changes in dendritic spines and contribute to neuronal death. However, mechanisms underlying structural and toxic effects are not fully understood. Here, we report that ADDLs bind to cultured mature cortical pyramidal neurons and induce spine dysgenesis. ADDL treatment induced the rapid depletion of kalirin-7, a brain-specific guanine-nucleotide exchange factor for the small GTPase Rac1, from spines. Kalirin-7 is a key regulator of dendritic spine morphogenesis and maintenance in forebrain pyramidal neurons and here we show that overexpression of kalirin-7 prevents ADDL-induced spine degeneration. Taken together, our results suggest that kalirin-7 may play a role in the early events leading to synapse degeneration, and its pharmacological activation may prevent or delay synapse pathology in AD.
Identifiants
pubmed: 30565792
doi: 10.1111/ejn.14311
pmc: PMC6559832
mid: NIHMS1002751
doi:
Substances chimiques
Amyloid beta-Peptides
0
Guanine Nucleotide Exchange Factors
0
Kalrn protein, rat
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1091-1101Subventions
Organisme : NIMH NIH HHS
ID : R01 MH071316
Pays : United States
Organisme : NIH-NIMH
ID : 5R01MH071316-10
Pays : International
Informations de copyright
© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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