TY - JOUR
T1 - Pin1 mediates Aβ42-induced dendritic spine loss
AU - Stallings, Nancy R.
AU - O'Neal, Melissa A.
AU - Hu, Jie
AU - Kavalali, Ege T.
AU - Bezprozvanny, Ilya
AU - Malter, James S.
N1 - Funding Information:
This work was supported by the Senator Betty and Dr. Andy Andujar Endowment and the NIH (P01HL88594 to J.S.M. and R01AG055577 to I.B. and E.T.K.). Author contributions: N.R.S., M.A.O., E.T.K., I.B., and J.S.M. designed the project. N.R.S. and M.A.O. performed the experiments and analyzed the data along with J.S.M. J.H. generated and maintained the Pinfl/fl mice. N.R.S., M.A.O., and J.S.M. wrote the manuscript with contributions from E.T.K. and I.B. All authors commented on and approved the final version. Competing interests: I.B. is a consultant for Teva Pharmaceutical Industries. The other authors declare that they have no competing interests.
Publisher Copyright:
Copyright © 2018 The Authors, All rights reserved.
PY - 2018/3/20
Y1 - 2018/3/20
N2 - Early-stage Alzheimer's disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that dendritic spine loss is induced by soluble, multimeric amyloid-β (A?β2), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. We investigated how calcineurin caused spine pathology and found that the cis-Trans prolyl isomerase Pin1 was a critical downstream target of Aβ42-calcineurin signaling. In dendritic spines, Pin1 interacted with and was dephosphorylated by calcineurin, which rapidly suppressed its isomerase activity. Knockout of Pin1 or exposure to A?42 induced the loss of mature dendritic spines, which was prevented by exogenous Pin1. The calcineurin inhibitor FK506 blocked dendritic spine loss in Aβ42-Treated wild-Type cells but had no effect on Pin1-null neurons. These data implicate Pin1 in dendritic spine maintenance and synaptic loss in early Alzheimer's disease.
AB - Early-stage Alzheimer's disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that dendritic spine loss is induced by soluble, multimeric amyloid-β (A?β2), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. We investigated how calcineurin caused spine pathology and found that the cis-Trans prolyl isomerase Pin1 was a critical downstream target of Aβ42-calcineurin signaling. In dendritic spines, Pin1 interacted with and was dephosphorylated by calcineurin, which rapidly suppressed its isomerase activity. Knockout of Pin1 or exposure to A?42 induced the loss of mature dendritic spines, which was prevented by exogenous Pin1. The calcineurin inhibitor FK506 blocked dendritic spine loss in Aβ42-Treated wild-Type cells but had no effect on Pin1-null neurons. These data implicate Pin1 in dendritic spine maintenance and synaptic loss in early Alzheimer's disease.
UR - http://www.scopus.com/inward/record.url?scp=85044249441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044249441&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aap8734
DO - 10.1126/scisignal.aap8734
M3 - Article
C2 - 29559586
AN - SCOPUS:85044249441
SN - 1937-9145
VL - 11
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
IS - 522
M1 - eaap8734
ER -