Background: Although genetic and biochemical studies have suggested a cardinal role for β-amyloid (Aβ) in Alzheimer’s disease, the underlying mechanism(s) of how Aβ induces neurodegeneration is still unclear. Our objective was to investigate the consequences of Aβ, especially on tau phosphorylation at specific epitopes important for Alzheimer’s disease. Methods: We used cortices from Tg2576 mice at 7 days to 15 months of age. Results: MALDI-TOF MS revealed an age-dependent shift in the Aβ isoform pattern. Young animals displayed high cortical levels of the shorter Aβ isoforms (Aβ1–16 and Aβ1–17) compared to 15-month-old Tg2576 mice which mainly expressed Aβ1–40 and Aβ1–42. The Aβ1–42 showed an age-dependent increase, whereas total Aβ1–40 levels remained constant. The highest levels of TBS-soluble Aβ oligomers were found at 90 days of age. Brain Aβ build-up did not affect the phosphorylation of tau at the epitopes investigated. Conclusions: This study provides new information about age-dependent Aβ isoforms and oligomers as well as their effect on site-specific tau phosphorylation in this transgenic mouse model. Our observations suggest that the different human Aβ isoforms do not directly cause increased tau phosphorylation and that the cognitive deficits seen in this mouse model are only related to the Aβ overexpression.

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