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

Melissa A O'Neal1, Nancy R Stallings1, James S Malter1

  • 1Department of Pathology, O'Donnell Brain Institute , UT Southwestern Medical Center , Dallas , Texas 75390-9072 , United States.

ACS Chemical Neuroscience
|May 15, 2018
PubMed

Insights

Excessive calcineurin (CN) activation drives Alzheimer's disease (AD) pathology by suppressing Pin1, leading to synapse loss. FK506, a CN inhibitor, rescues Pin1 function and synapse numbers, suggesting potential AD treatment.

Area of Science:

  • Neuroscience
  • Pathology
  • Pharmacology

Background:

  • Alzheimer's disease (AD) lacks effective therapeutics.
  • Excessive calcineurin (CN) activation is implicated in early AD pathogenesis.
  • CN-mediated dephosphorylation suppresses prolyl isomerase Pin1 via Aβ42 signaling.

Purpose of the Study:

  • To investigate the role of CN and Pin1 in AD pathology.
  • To evaluate FK506 as a potential therapeutic agent for AD.

Main Methods:

  • Review of in vitro, animal, and human studies.
  • Analysis of CN-mediated dephosphorylation of Pin1.
  • Assessment of FK506's effect on Pin1 activity and synaptic integrity.
  • Epidemiological data on AD incidence in FK506-treated transplant recipients.

Main Results:

  • CN activation suppresses Pin1, leading to dendritic spine and synapse loss characteristic of early AD.
  • FK506, a CN inhibitor, rescues Pin1 activity and restores synapse and dendritic spine numbers.
  • Chronic FK506 treatment in transplant recipients correlates with significantly lower AD incidence.

Conclusions:

  • Targeting CN with FK506 may preserve Pin1 function and synaptic health in early AD.
  • Prospective clinical trials are warranted to assess FK506's efficacy in treating AD.
  • FK506 represents a promising therapeutic strategy for Alzheimer's disease.
Keywords:
Alzheimer’s diseaseFK506Pin1calcineurindendritic spines

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