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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1233-1234 |
| Number of pages | 2 |
| Journal | ACS Chemical Neuroscience |
| Volume | 9 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 20 2018 |
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Keywords
- Alzheimer's disease
- calcineurin
- dendritic spines
- FK506
- Pin1
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Cognitive Neuroscience
- Cell Biology
Cite this
Alzheimer's Disease, Dendritic Spines, and Calcineurin Inhibitors : A New Approach? / O'Neal, Melissa A.; Stallings, Nancy R.; Malter, James S.
In: ACS Chemical Neuroscience, Vol. 9, No. 6, 20.06.2018, p. 1233-1234.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Alzheimer's Disease, Dendritic Spines, and Calcineurin Inhibitors
T2 - A New Approach?
AU - O'Neal, Melissa A.
AU - Stallings, Nancy R.
AU - Malter, James S.
PY - 2018/6/20
Y1 - 2018/6/20
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - calcineurin
KW - dendritic spines
KW - FK506
KW - Pin1
UR - http://www.scopus.com/inward/record.url?scp=85048820576&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048820576&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.8b00213
DO - 10.1021/acschemneuro.8b00213
M3 - Review article
C2 - 29757603
AN - SCOPUS:85048820576
VL - 9
SP - 1233
EP - 1234
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 6
ER -