Aerobic exercise improves lysosomal function in the brain of high cholesterol diet-fed APP/PS1 mice by modulating 27-hydroxycholesterol via the liver-brain axis

Typical pathological features of Alzheimer's disease include disturbances in cholesterol metabolism and defects in lysosomal function in the brain. With age and disease progression, patients with Alzheimer's disease have decreased cholesterol synthesis in the brain and abnormal cholesterol accumulation in neurons, accompanied by elevated 27-hydroxycholesterol concentrations. High-cholesterol diets are more common in Alzheimer's disease patients, which may promote the accumulation of 27-hydroxycholesterol and further exacerbate the disturbance of cholesterol metabolism in the brain. This leads to the entry of 27-hydroxycholesterol into the brain through the blood-brain barrier, where it disrupts lysosomal and synaptic function and ultimately exacerbates neuronal damage and Aβ deposition, contributing to cognitive decline. However, the mechanism underlying elevated 27-hydroxycholesterol concentrations and its relationship with lysosomal dysfunction have not been fully elucidated. In this study, we investigated the role of exercise in modulating peripheral and brain 27-hydroxycholesterol concentrations through a 12-week treadmill aerobic exercise intervention in mice. We found that aerobic exercise improved the function of cholesterol-metabolizing enzymes and restored lysosomal function. Exercise regulates 27-hydroxycholesterol levels through the liver-brain axis and reduces damage to neuronal and synaptic functions, providing new ideas for intervention in neurodegenerative diseases such as Alzheimer's disease.