Alzheimer's Disease, Dendritic Spines, and Calcineurin Inhibitors: A New Approach?

ACS Chemical Neuroscience
Melissa A O'NealJames S Malter

Abstract

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 Pin1 is suppressed by CN-mediated dephosphorylation induced by Aβ42 signaling. Pin1 loss directly leads to the reductions in dendritic spines and synapses characteristic of early AD pathology. Pin1 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 Pin1 function and support synaptic health in early AD.

References

Sep 25, 2015·Journal of Alzheimer's Disease : JAD·Giulio TaglialatelaLuca Cicalese
Feb 26, 2016·Annual Review of Pathology·Jochen Herms, Mario M Dorostkar
Apr 25, 2016·Ageing Research Reviews·Christopher M HenstridgeTara L Spires-Jones
Sep 30, 2016·Cellular and Molecular Life Sciences : CMLS·Syed Zahid Ali ShahLifeng Yang
Mar 22, 2018·Science Signaling·Nancy R StallingsJames S Malter

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