Elevation of cortical C26:0 due to the decline of peroxisomal β-oxidation potentiates amyloid β generation and spatial memory deficits via oxidative stress in diabetic rats.

Diabetes mellitus correlates with subsequent development of Alzheimer's disease (AD). An accumulation of very long chain fatty acids (VLCFAs) was observed in AD brains. We found previously that inhibiting peroxisomal β-oxidation by an inhibitor caused increases in VLCFA and β-amyloid peptide (Aβ) in the cortex and primary cultured neurons of rats. Therefore, we investigated whether there was an impaired peroxisomal β-oxidation and elevated VLCFA related to the increased Aβ in the diabetic brain. This study was conducted in a type 2 diabetic rat model induced by a high-fat diet and low-dose streptozotocin. A decrease in peroxisomal β-oxidation activity caused by down-regulated thiolase expression and a consequent increase in C26:0 were observed. Meanwhile, decreases in eicosapentenoic acid (EPA) and increases in oxidative stress [indicated by levels of malondialdehyde (MDA), and the protein expression of NOX4, p47(phox) and HO-1], Aβ, and the expression of AβPP and BACE1, two proteins involved in Aβ production, were observed. C26:0 levels were positively correlated with Aβ and MDA. This work suggests that in addition to decreases in EPA, increases in C26:0 by impaired peroxisomal β-oxidation can be a potential risk factor contributing to the progression of AD in diabetic brains via inducing oxidative stress.