Dataset Information

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response.

ABSTRACT:

Background

Current treatments for Alzheimer's disease (AD) have largely failed to yield significant therapeutic benefits. Novel approaches are desperately needed to help address this immense public health issue. Data suggests that early intervention at the first stages of mild cognitive impairment may have a greater chance for success. The calcineurin (CN)-Pin1 signaling cascade can be selectively targeted with tacrolimus (FK506), a highly specific, FDA-approved CN inhibitor used safely for > 20 years in solid organ transplant recipients. AD prevalence was significantly reduced in solid organ recipients treated with FK506.

Methods

Time release pellets were used to deliver constant FK506 dosage to APP/PS1 mice without deleterious manipulation or handling. Immunofluorescence, histology, molecular biology, and behavior were used to evaluate changes in AD pathology.

Results

FK506 can be safely and consistently delivered into juvenile APP/PS1 mice via time-release pellets to levels roughly seen in transplant patients, leading to the normalization of CN activity and reduction or elimination of AD pathologies including synapse loss, neuroinflammation, and cognitive impairment. Pin1 activity and function were rescued despite the continuing presence of high levels of transgenic Aβ₄₂. Indicators of neuroinflammation including Iba1 positivity and IL-6 production were also reduced to normal levels. Peripheral blood mononuclear cells (PBMC) obtained during treatment or splenocytes isolated at euthanasia activated normally after mitogens.

Conclusions

Low-dose, constant FK506 can normalize CNS CN and Pin1 activity, suppress neuroinflammation, and attenuate AD-associated pathology without blocking peripheral IL-2 responses making repurposed FK506 a viable option for early, therapeutic intervention in AD.

SUBMITTER: Stallings NR

PROVIDER: S-EPMC10580561 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response.

Stallings Nancy R NR O'Neal Melissa A MA Hu Jie J Shen Zhong-Jian ZJ Malter James S JS

Alzheimer's research & therapy 20231017 1

<h4>Background</h4>Current treatments for Alzheimer's disease (AD) have largely failed to yield significant therapeutic benefits. Novel approaches are desperately needed to help address this immense public health issue. Data suggests that early intervention at the first stages of mild cognitive impairment may have a greater chance for success. The calcineurin (CN)-Pin1 signaling cascade can be selectively targeted with tacrolimus (FK506), a highly specific, FDA-approved CN inhibitor used safely ...[more]

PMID: 37849016

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Dataset Information

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response.

Background

Methods

Results

Conclusions

Publications

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response.

Similar Datasets

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