Abstract
BackgroundThe relationship between the pathogenic amyloid β-peptide species Aβ1–42 and tau pathology has been well studied and suggests that Aβ1–42 can accelerate tau pathology in vitro and in vivo. The manners if any in which Aβ1–40 interacts with tau remains poorly understood. In order to answer this question, we used cell-based system, transgenic fly and transgenic mice as models to study the interaction between Aβ1–42 and Aβ1–40.ResultsIn our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to Aβ1–42 induced cleavage, phosphorylation and aggregation of wild-type/full length tau while exposure to Aβ1–40 didn’t. Functional studies with Aβ1–40 were carried out in tau-GFP transgenic flies and showed that Aβ1–42, as previously reported, disrupted cytoskeletal structure while Aβ1–40 had no effect at same dose. To further explore how Aβ1–40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either Aβ1–42 or Aβ1–40. We found that treatment with Aβ1–42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice. By contrast, Aβ1–40 injection didn’t alter total tau, phospho-tau (recognized by PHF-1) or cleavage of tau, but interestingly, phosphorylation at Ser262 was shown to be significantly decreased after direct inject of Aβ1–40 into the entorhinal cortex of P301S mice.ConclusionsThese results demonstrate that Aβ1–40 plays different role in tau pathogenesis compared to Aβ1–42. Aβ1–40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser262, which has been shown to be neurotoxic.
Highlights
The relationship between the pathogenic amyloid β-peptide species Aβ1–42 and tau pathology has been well studied and suggests that Aβ1–42 can accelerate tau pathology in vitro and in vivo
It is generally believed that amyloid-β peptides (Aβ) accrual in brain is an early event in the pathogenesis of Alzheimer’s disease (AD), preceding significant tau pathology
Increasing experimental evidence on differential roles that Aβ1-40 and Aβ1-42 may play in amyloid deposition raises the question of whether Aβ1-40 alters tau phosphorylation and/or aggregation in the same manner as Aβ1-42. We address this issue by using: 1) a cell-based model to study the effects of Aβ1-42 and Aβ1-40 on tau aggregation using live cell imaging; 2) a transgenic Drosophila model to examine the direct impact on cytoskeleton structure caused by Aβ1-42 and Aβ1-40; 3) a tau transgenic mouse model to compare the effects of Aβ1-42 and Aβ1-40 on tau pathogenesis
Summary
The relationship between the pathogenic amyloid β-peptide species Aβ1–42 and tau pathology has been well studied and suggests that Aβ1–42 can accelerate tau pathology in vitro and in vivo. Dimers, isolated from a human AD brain, were sufficient to induce tau hyperphosphorylation at AD-relevant epitopes as well as microtubule disruption and neuritic degeneration [3]. These experiments were done either with Aβ1-42 or a mixture of Aβ1-42 and Aβ1-40; increasing evidence suggests that Aβ1-40 and Aβ1-42 differentially contribute to the disease process [4]. Emerging evidence indicates a protective role for Aβ1-40 in AD pathogenesis One such theory suggests that Aβ1-40 may act to stabilize Aβ1-42 monomers by competing for binding sites on pre-existing Aβ1-42 aggregates [7] and thereby inhibiting further aggregation of Aβ1-42 [8]
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