Chronic exposure to mild therapeutic hypothermia prevents cognitive deterioration and neurodegeneration in a rat model of AD‐like pathology

Abstract Background Mechanisms of epigenetic regulation modulate gene expression without alterations in the genomic sequence and play important roles in brain development 1 , synaptic plasticity and memory 2 . Epigenetic regulation of gene transcription would be an appropriate mechanism for cells to flexibly adapt to the environmental changes. In this context, lysine specific demethylase 1 (LSD1) is an important enzyme that modifies gene transcription 3 . Recently, it was reported that LSD1 is essential for the regulation of neuronal gene transcriptional programs involved in synaptic plasticity and cognition 2–4 . Despite, the well‐known function of LSD1 in early development 1,4–6 , there is some controversy about the specific role of LSD1 in aging. Upon cold exposure LSD1 regulates Brown adipose tissue function and mediates beige adipogenesis to increase thermogenic capacity and prevent changes in body temperature by inducing non‐shivering thermogenesis 7 . However, the role of repeat cold exposures on brain LSD1 function has never been studied. We investigated whether chronic repeat cold exposures could modulate the hippocampal expression of LSD1 and its potential impact on neurodegeneration and cognitive functions, using non‐transgenic (non‐tg) and transgenic (tg) AD‐like rat model. Method McGill‐R‐Thy1‐APP‐tg rats exhibited accumulation of intraneuronal Aβ peptide, display cognitive deficits and reproduce an AD‐like amyloid pathology. Thus,17 months tg and non‐tg rats were expose under therapeutic hypothermia for 2 hours at 4°C daily during 1 month. Result Our results demonstrated how progressive intraneuronal Aβ accumulation correlates with upregulation of LSD1 at early stages (prior plaques formation) of the AD‐like amyloid pathology, which impact on the alteration of cognitive functions. We showed that chronic mild therapeutic hypothermia modulates hippocampal LSD1 levels, improving synaptic plasticity and preventing cognitive dysfunction. Conclusion Taken together our work suggests that modulating brain LSD1 levels through repeat cold exposures constitute a novel non‐pharmacological therapeutic strategy to prevent neurodegeneration and preserve cognitive functions. (1) Toffolo E, et al. J Neurochem . 2014; (2) Wang J, et al. Nat Neurosci . 2016; (3) Lim CS, Nam HJ, et al . Sci Rep . 201 7; (4) Rusconi F, et al. Trends Neurosci . 2017; (5) Maes T, et al. Epigenomics . 2015; (6) Ciceri F, et al. Curr Pharm Des . 2017; (7) Marcher AB, et al. Cell Rep . 2015.