Amphiphysin I cleavage by asparagine endopeptidase leads to tau hyperphosphorylation and synaptic dysfunction.
Alzheimer Disease
/ enzymology
Animals
Behavior, Animal
Brain
/ enzymology
COS Cells
Case-Control Studies
Chlorocebus aethiops
Cognition
Cyclin-Dependent Kinase 5
/ metabolism
Cysteine Endopeptidases
/ genetics
Disease Models, Animal
HEK293 Cells
Humans
Maze Learning
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins
/ genetics
Neurons
/ enzymology
Phosphorylation
Rats
Synapses
/ enzymology
tau Proteins
/ genetics
Alzheimer's disease
amphiphysin Ⅰ
cell biology
endocytosis
human
mouse
neuroscience
synaptic dysfunction
tau
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
21 05 2021
21 05 2021
Historique:
received:
29
11
2020
accepted:
28
04
2021
entrez:
21
5
2021
pubmed:
22
5
2021
medline:
21
10
2021
Statut:
epublish
Résumé
Neurofibrillary tangles composed of hyperphosphorylated tau and synaptic dysfunction are characteristics of Alzheimer's disease (AD). However, the underlying molecular mechanisms remain poorly understood. Here, we identified Amphiphysin I mediates both tau phosphorylation and synaptic dysfunction in AD. Amphiphysin I is cleaved by a cysteine proteinase asparagine endopeptidase (AEP) at N278 in the brains of AD patients. The amount of AEP-generated N-terminal fragment of Amphiphysin I (1-278) is increased with aging. Amphiphysin I (1-278) inhibits clathrin-mediated endocytosis and induces synaptic dysfunction. Furthermore, Amphiphysin I (1-278) binds p35 and promotes its transition to p25, thus activates CDK5 and enhances tau hyperphosphorylation. Overexpression of Amphiphysin I (1-278) in the hippocampus of Tau P301S mice induces synaptic dysfunction, tau hyperphosphorylation, and cognitive deficits. However, overexpression of the N278A mutant Amphiphysin I, which resists the AEP-mediated cleavage, alleviates the pathological and behavioral defects. These findings suggest a mechanism of tau hyperphosphorylation and synaptic dysfunction in AD.
Identifiants
pubmed: 34018922
doi: 10.7554/eLife.65301
pii: 65301
pmc: PMC8139826
doi:
pii:
Substances chimiques
MAPT protein, human
0
Mapt protein, mouse
0
Nerve Tissue Proteins
0
tau Proteins
0
amphiphysin
147954-52-7
Cyclin-Dependent Kinase 5
EC 2.7.11.1
Cysteine Endopeptidases
EC 3.4.22.-
asparaginylendopeptidase
EC 3.4.22.34
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2021, Zhang et al.
Déclaration de conflit d'intérêts
XZ, LZ, LM, MX, LP, GC, YZ, JX, ZW, DD, ZZ, XC, TW, LT, KY, ZZ No competing interests declared
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