Chronic exposure to mild terapeutic hypothermia prevents cognitive deterioration and neurodegeneration un a rat model of AD-like pathology

BEATRIZ BISTUE; RAMIRO AVILA; MARTIN A. BRUNO

Congreso; Alzheimer's Association International Conference.; 2020

Background: Recently it has been demonstrated that irisin, a new discovered skeletal muscle-derived myokine, isdecreased in the hippocampus of postmortem brain tissue from people with early and late-stages of AD. Researchersfound less irisin in the CSF of people with MCI and AD than in controls, whereas irisin ran higher among older peoplewith normal cognition. Exercise-linked irisin exerted protective actions in the brains of AD animal models, rescuingsynaptic plasticity and memory defects1,2. The widely distributed neurotrophin in the brain, BDNF; has been known toplay a critical role in synaptic function, learning, memory and neuronal survival3-6. Interestingly, irisin is the upstreammediator of BDNF production and triggers its brain expression upon aerobic excercise7, improving memory inpersons with intact cognition, MCI or dementia4–6. Bolstering brain irisin levels, either pharmacologically or throughaerobic exercise, may constitute a novel non-pharmacological therapeutic strategy to protect and/or repair synapsefunction or prevent cognitive decline. In this regards, previous reports demonstrated that cold exposure induced irisinsecretion in human, proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. Thus, wehypothesized that repeated cold exposures may contribute to delay disease progression, representing a potentialtarget for AD. So, we designed a non-pharmacological therapeutic strategy applying chronic mild hypothermia toinduce neuroprotection and improve cognitive functions in our transgenic AD-like model.Method: 17 months old transgenic McGill-R-Thy1-APP rats were chronically exposed to a mild hypothermic treatmentat 4°C 2hs daily during 28 consecutive days. Irisin and BDNF levels were measured by ELISA from plasma andhippocampal homogenates. By Immunohistochemistry, quantification of synaptophysin-immunoreactivity presynapticboutons were compared between controls vs. AD-like treated rats. A hippocampal memory task was performed byNovel objects Recognition (NOR) test.Result: Our results demonstrated that chronic exposure to a mild hypothermia bolstered Irisin and BDNFhippocampal and plasma levels, increase synaptophysin-positive presynaptic boutons expression and improvecognitive functions.Conclusion: A controlled and repeated mild‐hypothermia constitute a novel non-pharmacological therapeutic strategyto modulate Irisin levels, prevent neurodegeneration and preserve cognitive functions.