PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
26 05 2021
26 05 2021
Historique:
received:
03
01
2020
revised:
22
09
2020
accepted:
09
01
2021
entrez:
27
5
2021
pubmed:
28
5
2021
medline:
13
7
2021
Statut:
ppublish
Résumé
Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer's disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.
Identifiants
pubmed: 34039738
pii: 13/595/eaba7394
doi: 10.1126/scitranslmed.aba7394
pmc: PMC8988215
mid: NIHMS1787604
pii:
doi:
Substances chimiques
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
0
tau Proteins
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
Subventions
Organisme : NIA NIH HHS
ID : L30 AG074191
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095922
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG070075
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066462
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG055694
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG064244
Pays : United States
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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