Sustained high body temperature exacerbates cognitive function and Alzheimer’s disease-related pathologies

Abstract

Global warming is a serious public health threat to people worldwide. High body temperature is one of the important risk factors for Alzheimer’s disease (AD), and the body temperature of AD patients has been found to be significantly higher than that of elderly control subjects. However, the effects of high body temperature on cognitive function and AD pathologies have not been completely elucidated. We report here that Tg2576 mice housed at a high ambient temperature of 30 °C for 13 months showed an increase in the body temperature, which is accompanied by memory impairment and an enhancement of amyloid-β peptides (Aβ) generation through the upregulation of β-site APP cleaving enzyme 1 (BACE1) level and decrease in the level of an Aβ-degrading enzyme, neprilysin (NEP) in the brain, compared with those of Tg2576 mice at 23 °C. High body temperature also increased the levels of heat shock proteins (HSPs), stress-stimulated kinases such as JNK, and total tau, leading to the enhancement of tau phosphorylation at 30 °C. Taken together, our findings suggest that high body temperature exacerbates cognitive function and AD pathologies, which provides a mechanistic insight for its prevention.

IF1 Protein Controls Aging Rate

“…In a mouse model of Alzheimer’s disease (AD), raising body temperature (by 0.50–0.79°C) results in enhanced BACE1 expression, more amyloid beta (Aβ) generation, greater Aβ plaque area, greater amount and hyperphosphorylation of tau, and worse memory (in a maze task. “Our study highlights an impact of high body temperature on the progression of AD pathologies, providing a mechanistic insight for its prevention”) [192]. From early in disease progression, mice of a mouse model of Alzheimer’s have greater mean body temperature than control mice (0.2-0.4°C more, statistically significant), which cannot be lowered by ibuprofen (an antipyretic) administration [193].…”

“…When instead starting drug administration at 18 months old, assessed at 24 months old, there was failure to reduce Aβ plaque amount [287]). To contrast, in mice of the same mouse model of Alzheimer’s (Tg2576, starting at 4 months old, assessed at 17 months old), those with a body temperature of 0.50–0.79°C ( middle of this range is 0.65°C, which is less than the variation in resting body temperature across different humans [158, 168]) lower had up to 50% less Aβ plaque amount in their cortex and hippocampus (Figure 3a in [192]). Distinctly, whilst there is no published data showing that aducanumab can improve cognition in a mouse model of Alzheimer’s disease, there is such data for a slightly lower body temperature, showing that it confers better memory [192].…”

“…To summarize: Alzheimer’s patients can have higher body temperature [194], where higher body temperature has been shown to accelerate/exacerbate the disease in a mouse model of Alzheimer’s (e.g., causing greater Aβ plaque area and worse memory) [192]. A selective F 1 F 0 ATP hydrolysis inhibiting drug ( that doesn’t inhibit F 1 F 0 ATP synthesis ) can ( if ambient temperature is sufficiently low, e.g.…”

“…Assaying whether this drug can reduce the pathologically high body temperature of Alzheimer's disease [194] to normality. If it can, this should be sufficient for clinical approval, for helping patients with Alzheimer's disease (especially because data suggests that higher body temperature accelerates Alzheimer's disease progression [192]). Optionally screening a population of Alzheimer's patients and (by setting the inclusion/exclusion criteria as such) only admitting those with the highest body temperatures into the clinical trial.…”

“…Unity Biotechnology showed that UBX0101 could decrease senescent cell number after knee injury in mice (but this couldn't be replicated in rats or dogs) and extrapolated that UBX0101 would treat osteoarthritis[353]. Endpoint for an osteoarthritis clinical trial is typically patient selfreporting pain (e.g., using the WOMAC scoring scale questionnaire), for which the Alzheimer's disease can cause a higher body temperature in humans[194].Higher body temperature accelerates disease progression in a mouse model of Alzheimer's[192]. A clinical trial can use the objective endpoint of body temperature (as an endpoint itself.…”