Dietary high salt drives cognitive impairment and Aβ accumulation via an insufficient compensatory mitophagy response

There is mounting evidence that dietary habits are strongly correlated with cerebrovascular diseases and dementia, but the precise mechanism remains unclear how a salt-rich diet adversely affects the brain. Here, 12-month-old mice were fed a high-salt diet (HSD) for 2 months, and we observed salt-induced cognitive deficits in mice. The short-term HSD increased mitophagy-associated markers (PINK1, Parkin, and LC3-II) and decreased SQSTM1/p62, consistent with a compensatory mitophagy response that was insufficient to prevent cognitive decline. Neuro-2a cells were cultured in normal medium, NaCl medium (40 mM) or NaCl (40 mM) + CCCP group (20 μM) medium for 24 h, respectively. Short-term HSD feeding impaired learning and memory and increased amyloid-β (Aβ) burden, in parallel with altered PINK1/Parkin-associated mitophagy markers. These findings link a salt-rich diet to cognitive dysfunction, and suggest that enhancing PINK1/Parkin-mediated mitophagy may counteract the harmful effects of HSD on the brain. Therefore, the PINK1/Parkin mitophagy may be a potential target for combating the harmful effects on the brain caused by HSD or other diseases related to mitophagy.