# The impact of high-intensity interval training on cerebrovascular function in the APP/PS1 mice

## TL;DR

High-intensity interval training improves cerebrovascular function and reduces Alzheimer's disease pathology in mice.

## Contribution

This study demonstrates that HIIT can ameliorate AD pathology and cognitive decline through cerebrovascular and metabolic mechanisms.

## Key findings

- HIIT reduced AD pathological markers and improved memory in APP/PS1 mice.
- HIIT enhanced pro-angiogenic signaling and vasodilation in the hippocampus.
- HIIT increased HIF-1α expression, suggesting a role in hypoxic metabolism.

## Abstract

Alzheimer’s disease (AD), the most commonly diagnosed form of senile dementia worldwide, is closely associated with aging and distinct neuropathological features. Recent studies highlight that up to 90% of individuals, either preclinical or clinical, diagnosed with vascular pathology in the context of AD exhibit thickening and hyalinization of the media in small and medium-sized cerebral vessels. Exercise has emerged as a potential, non-pharmaceutical, and cost-effective intervention for the prevention and treatment of AD. However, there is limited research exploring the effects of high-intensity interval training (HIIT) on cerebrovascular function in AD.

Four-month-old female C57BL/6 J mice and APP/PS1 transgenic mice were initially acclimated to a standard diet for 1 week. The two groups were then divided into sedentary and exercise cohorts, with the exercise group engaging in a 6-week HIIT regimen. Post-intervention, hippocampal specimens were collected for analysis. Aβ and Tau protein levels were measured to assess AD pathology, while cognitive function was evaluated using the eight-arm radial maze and BDNF mRNA expression. Additionally, markers of cerebrovascular function-including VEGF, EPO, eNOS, GPR68, and ET-1-were examined, and HIF-1α was utilized to assess the hippocampal response to AD pathology.

HIIT significantly reduced reference memory errors (p = 0.025) and markedly upregulated Bdnf mRNA expression (p < 0.001) specifically in APP/PS1 mice. Furthermore, HIIT significantly decreased protein levels of AD pathological markers p-TAU (p = 0.001) and APP (p = 0.002) in APP/PS1 mice. HIIT significantly increased the mRNA (p < 0.001) and protein (p = 0.003) levels of EPO and Vegfa mRNA (p < 0.001) levels to stimulate pro-angiogenic signal in APP/PS1 mice. HIIT also significantly increased both the mRNA and proteins levels of eNOS expression (p < 0.001) while decreasing the mRNA and proteins levels of ET-1 (p < 0.001) and GPR68 (p < 0.001) to enhance vasodilation in APP/PS1 mice. Finally, HIIT significantly increased HIF-1α expression at both protein and mRNA levels (p < 0.001), independent of genotype.

HIIT ameliorates cognitive function and reduces hallmark AD pathology. This positive effect is potentially mediated through cerebral microangiogenesis, cerebrovascular function regulation, and hypoxic metabolism. HIIT represents a promising non-pharmacological strategy for targeting multiple aspects of AD pathophysiology.