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Pin1 mediates A?42-induced dendritic spine loss.


ABSTRACT: 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-? (A?42), 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 A?42-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 A?42-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.

SUBMITTER: Stallings NR 

PROVIDER: S-EPMC6136423 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Pin1 mediates Aβ<sub>42</sub>-induced dendritic spine loss.

Stallings Nancy R NR   O'Neal Melissa A MA   Hu Jie J   Kavalali Ege T ET   Bezprozvanny Ilya I   Malter James S JS  

Science signaling 20180320 522


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 (Aβ<sub>42</sub>), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. We investigated how c  ...[more]

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