期刊
ACS CHEMICAL NEUROSCIENCE
卷 9, 期 6, 页码 1233-1234出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00213
关键词
Alzheimer's disease; calcineurin; dendritic spines; Pin1; FK506
Therapeutics to effectively treat Alzheimer's disease (AD) are lacking. In vitro, animal and human studies have implicated the excessive activation of the protein phosphatase calcineurin (CN) as an early step in the pathogenesis of AD. We discuss recent data showing that the prolyl isomerase Pinl is suppressed by CN-mediated dephosphorylation induced by A beta 42 signaling. Pinl loss directly leads to the reductions in dendritic spines and synapses characteristic of early AD pathology. Pinl activity, and synapse and dendritic spine numbers are rescued by FK506, a highly specific and United States Food and Drug Administration approved CN inhibitor. Solid organ transplant recipients chronically treated with FK506 showed much lower AD incidence than expected. As such, we suggest prospective clinical trials to determine if systemic FK506 can normalize CN activity in the brain, preserve Pinl function and support synaptic health in early AD.
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