We report a post mortem biochemical analysis of amyloid-β (Aβ) (ELISA) and tau (Western immunoblots) in the temporo-parietal neocortex of subjects with a clinical diagnosis of mild cognitive impairment (MCI, n = 12), Alzheimer's disease (AD, n = 12) or no cognitive impairment (NCI, n = 12). Levels of Aβ42 in the detergent-insoluble protein fractions were significantly higher in persons with AD but did not differentiate individuals with MCI. Conversion of tau into its insoluble form (soluble/insoluble tau ratio) or into paired helical filament tau (PHFtau) were the biochemical variables most closely related to clinical and neuropathological diagnoses, but they did not distinguished MCI from the two other groups. Interestingly, soluble/insoluble total tau ratio, PHFtau and insoluble Aβ42 concentrations in the cortex correlated strongly with global cognition scores proximate to death and with immunohistochemical and histological quantification of Aβ and tau pathologies. Our data suggest that 1) insoluble Aβ42 and insoluble tau (total or PHFtau) show a significant relationship with the clinical and neuropathological diagnosis of AD; 2) Although MCI appears to represent an intermediate stage between NCI and AD, the quantification of cortical Aβ and tau pathologies did not significantly distinguish subjects with MCI from either group.
Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) and tau pathology and improves cognitive performance in animal models of Alzheimer's disease (AD). To exclude confounding variables associated with the diet, we crossed 3 × Tg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.001), including docosahexaenoic acid (DHA; +5%, p < 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels of soluble Aβ₄₂ (-41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ₄₀ and Aβ₄₂ in the brain of 3 × Tg-AD mice. The 3 × Tg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (-25%, p < 0.05) and insoluble phosphorylated tau (-55%, p < 0.05) compared to 3 × Tg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3 × Tg-AD/Fat-1 mice (-039%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, cyclin-dependent kinase 5, or protein phosphatase type 2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (-37%, p < 0.01) observed in 20 month-old 3 × Tg-AD mice. In conclusion, the expression of fat-1 in 3 × Tg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology.
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