Chronic sleep deprivation and zinc deficiency differentially affect amyloid processing in APP/PS1 mice

Background Alzheimer’s disease is characterized by amyloid-β plaque accumulation, which reflects an imbalance between amyloid-β production and clearance. Sleep disturbances and zinc dyshomeostasis have been associated with altered amyloid-β metabolism; however, their combined effects remain unclear. This study examined the single and combined effects of chronic sleep deprivation and dietary zinc deficiency on amyloid-β accumulation and related molecular pathways in APP/PS1 transgenic mice. Methods Twenty-four female APP/PS1 mice (9-month-old) were assigned to four groups (n = 6/group): control, sleep deprivation (5 h/day for 2 weeks), zinc-deficient diet (4 weeks), and combined sleep deprivation and zinc-deficient diet. Serum and brain zinc, copper, and iron concentrations were quantified using inductively coupled plasma mass spectrometry. Diethylamine-soluble and formic acid–insoluble amyloid-β1–42 levels were measured using an enzyme-linked immunosorbent assay. Brain parenchymal and endothelial-enriched fractions were used to assess proteins related to amyloid precursor protein processing and amyloid-β degradation/clearance using western blotting. Group effects and the sleep deprivation × zinc deficiency interaction were tested using two-way analysis of variance. Results Serum zinc concentrations decreased in the zinc-deficient diet groups, whereas brain zinc, copper, and iron concentrations remained unchanged. Soluble amyloid-β1–42 levels increased relative to the control only in the zinc-deficient diet group. Insoluble amyloid-β1–42 levels increased in all experimental groups compared to those in the control group, with the highest mean level observed in the combined exposure group. The interaction pattern did not indicate clear synergy. Conclusions Chronic sleep deprivation and dietary zinc deficiency differentially affect amyloid-β1–42 levels in APP/PS1 mice. These findings support the idea that sleep disturbance and micronutrient imbalance can independently influence amyloid-β production, aggregation, and clearance pathways, with combined exposure resulting in additive increases in insoluble amyloid-β burden.