Microglial Piezo1 senses Aβ fibril stiffness to restrict Alzheimer's disease.
The pathology of Alzheimer's disease (AD) is featured with extracellular amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca2+ influx for microglial clustering, phagocytosis, and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD.
Pubmed ID: 36368316 RIS Download
Research resources used in this publication
- mPiezo1-IRES-eGFP (RRID:Addgene_80925) (plasmid)
- B6.129P2(Cg)-Cx3cr1tm2.1(cre/ERT2)Litt/WganJ (RRID:IMSR_JAX:021160) (organism)
- B6;129-Piezo1tm1.1Apat/J (RRID:IMSR_JAX:029214) (organism)
- B6.Cg-Piezo1tm2.1Apat/J (RRID:IMSR_JAX:029213) (organism)
- HEK293T (RRID:CVCL_0063) (cell line)
- B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (RRID:MMRRC_034840-JAX) (organism)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Alpha Tubulin antibody (RRID:AB_11042766)
- CD45 Monoclonal Antibody (30-F11), PE-Cyanine7, eBioscience (RRID:AB_2734986)
- CD11b Monoclonal Antibody (M1/70), APC, eBioscience (RRID:AB_469342)
- Purified Rat Anti-Mouse CD16/CD32 (Mouse BD Fc Block™) Clone 2.4G2 (RRID:AB_394656)
- Anti-β-Actin Antibody (C4) (RRID:AB_626632)
- GAPDH (6C5) (RRID:AB_627679)
- APP C-Terminal Fragment Monoclonal Antibody, Purified (RRID:AB_10717336)
- PSD95 antibody (RRID:AB_298846)
- CD107a (LAMP-1) (RRID:AB_2134499)
- APC/Cyanine7 anti-mouse Ly-6C (RRID:AB_10640120)
- Integrin alpha3 (Ralph 3.2) (RRID:AB_668046)
- Anti-TMEM119 antibody [28-3] - Microglial marker (RRID:AB_2800343)
- PIEZO1 (extracellular domain) antibody (RRID:AB_2881161)
- Anti-Piezo1 Antibody (RRID:AB_2756743)
- Purified anti-Neurofilament H (NF-H), Phosphorylated (RRID:AB_2715851)
- Iba1 antibody (RRID:AB_2224402)
- Anti Iba1, Rabbit antibody (RRID:AB_839504)
- RFP Antibody Pre-adsorbed (RRID:AB_2209751)
Associated grants
NonePublication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
Alpha Tubulin antibody (antibody)
RRID:AB_11042766
This monoclonal targets Alpha Tubulin
View all literature mentionsCD45 Monoclonal Antibody (30-F11), PE-Cyanine7, eBioscience (antibody)
RRID:AB_2734986
This monoclonal targets CD45
View all literature mentionsCD11b Monoclonal Antibody (M1/70), APC, eBioscience (antibody)
RRID:AB_469342
This monoclonal targets CD11b
View all literature mentionsPurified Rat Anti-Mouse CD16/CD32 (Mouse BD Fc Block™) Clone 2.4G2 (antibody)
RRID:AB_394656
This monoclonal targets CD16/CD32
View all literature mentionsAnti-β-Actin Antibody (C4) (antibody)
RRID:AB_626632
This monoclonal targets β-Actin
View all literature mentionsGAPDH (6C5) (antibody)
RRID:AB_627679
This monoclonal targets GAPDH (6C5)
View all literature mentionsAPP C-Terminal Fragment Monoclonal Antibody, Purified (antibody)
RRID:AB_10717336
This monoclonal targets APP C-Terminal Fragment Purified
View all literature mentionsCD107a (LAMP-1) (antibody)
RRID:AB_2134499
This monoclonal targets Lamp1
View all literature mentionsAPC/Cyanine7 anti-mouse Ly-6C (antibody)
RRID:AB_10640120
This monoclonal targets Ly-6C
View all literature mentionsIntegrin alpha3 (Ralph 3.2) (antibody)
RRID:AB_668046
This monoclonal targets Integrin alpha3 (Ralph 3.2)
View all literature mentionsAnti-TMEM119 antibody [28-3] - Microglial marker (antibody)
RRID:AB_2800343
This monoclonal targets TMEM119
View all literature mentionsPIEZO1 (extracellular domain) antibody (antibody)
RRID:AB_2881161
This polyclonal targets PIEZO1 (extracellular domain)
View all literature mentionsAnti-Piezo1 Antibody (antibody)
RRID:AB_2756743
This unknown targets Piezo1 Channel
View all literature mentionsPurified anti-Neurofilament H (NF-H), Phosphorylated (antibody)
RRID:AB_2715851
This monoclonal targets Neurofilament H NF-H Phospho
View all literature mentionsAnti Iba1, Rabbit antibody (antibody)
RRID:AB_839504
This polyclonal targets Iba1
View all literature mentionsRFP Antibody Pre-adsorbed (antibody)
RRID:AB_2209751
This polyclonal targets RFP
View all literature mentionsB6.129P2(Cg)-Cx3cr1tm2.1(cre/ERT2)Litt/WganJ (organism)
RRID:IMSR_JAX:021160
Mus musculus with name B6.129P2(Cg)-Cx3cr1tm2.1(cre/ERT2)Litt/WganJ from IMSR.
View all literature mentionsB6;129-Piezo1tm1.1Apat/J (organism)
RRID:IMSR_JAX:029214
Mus musculus with name B6;129-Piezo1tm1.1Apat/J from IMSR.
View all literature mentionsB6.Cg-Piezo1tm2.1Apat/J (organism)
RRID:IMSR_JAX:029213
Mus musculus with name B6.Cg-Piezo1tm2.1Apat/J from IMSR.
View all literature mentionsHEK293T (cell line)
RRID:CVCL_0063
Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsB6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (organism)
RRID:MMRRC_034840-JAX
Mus musculus with name B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax from MMRRC.
View all literature mentions
