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.

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimer’s disease

“…1b-c), suggesting their changes with CI severity may be co-regulated with Ab and tau accumulation. In line with these results, previous studies have shown that Ab42 signaling promotes calcineurin activity 23 and interestingly, inhibition of calcineurin activity protects mice from Ab-and tau-induced synapse loss and CI 24,25 . Notably, SMOC1, an extracellular matrix protein previously linked to AD and Ab plaques 26,27 , was not associated with CI after adjusting for PTau181:Ab42 (Extended Data Fig.…”

“…We compared YWHAG:NPTX2 changes with normal aging -20-year binned age groups from young (age [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] to old (age 80-95) -and with AD progression -cognitively normal old (age 80-95) to moderate-severe CI (age 65-95). We found that YWHAG:NPTX2 increased by 1.9 standard deviations over 60 years of normal aging and then 2.7 standard deviations from aged to dementia (Fig.…”