Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation

Abstract

Aims To illuminate the pathological synergy between Aβ and tau leading to emergence of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), here, we have performed a comparative neuropathological study utilising three distinctive variants of human tau (WT tau, P301L mutant tau and S320F mutant tau). Previously, in non‐transgenic mice, we showed that WT tau or P301L tau does not form NFT while S320F tau can spontaneously aggregate into NFT, allowing us to test the selective vulnerability of these different tau conformations to the presence of Aβ plaques. Methods We injected recombinant AAV‐tau constructs into neonatal APP transgenic TgCRND8 mice or into 3‐month‐old TgCRND8 mice; both cohorts were aged 3 months post injection. This allowed us to test how different tau variants synergise with soluble forms of Aβ (pre‐deposit cohort) or with frank Aβ deposits (post‐deposit cohort). Results Expression of WT tau did not produce NFT or altered Aβ in either cohort. In the pre‐deposit cohort, S320F tau induced Aβ plaque deposition, neuroinflammation and synaptic abnormalities, suggesting that early tau tangles affect the amyloid cascade. In the post‐deposit cohort, contemporaneous expression of S320F tau did not exacerbate amyloid pathology, showing a dichotomy in Aβ‐tau synergy based on the nature of Aβ. P301L tau produced NFT‐type inclusions in the post‐deposit cohort, but not in the pre‐deposit cohort, indicating pathological synergy with pre‐existing Aβ deposits. Conclusions Our data show that different tau mutations representing specific folding variants of tau synergise with Aβ to different extents, depending on the presence of cerebral deposits.

Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer’s disease pathology

“…Mounting evidence gathered over the last two decades indicates that synergistic interactions between Aβ and tau, rather than effects of the individual protein may underlie the cause and progression of AD pathology 3 . This is supported by data showing that (i) Aβ accelerates tau phosphorylation and aggregation, (ii) complexes of Aβ bound to tau are detected in AD brain extracts, (iii) Aβ core region can bind directly to tau and (iv) Aβ aggregates can trigger/propagate tau pathology in cultured cells and animal models 12 – 15 . Notwithstanding the appearance of Aβ aggregates prior to tau pathology, the entwined nature of these two proteins necessitates an AD treatment strategy targeting simultaneously both proteins.…”

Distinct and joint effects of low and high levels of Aβ and tau deposition on cortical thickness

“…According to our hypothesis, when the effects of Aβ and tau overlap and synergize, the resonance between the two pathologies can be detected by assessing the spatial similarity between their pattern of accumulation throughout the entire cerebral cortex, which eventually can lead to cognitive decline. This hypothesis is supported by significant basic science work showing that the combination of Aβ and tau that leads to neurodegeneration, via mechanisms including microglial activation, synaptic spine loss, and suppression of neuronal activity, while either protein in isolation is often compatible with normal functioning [61, 67]. One limitation of this study is that the Aβ PET tracer in HC (18F-Florbetaben) and MCI (18F-Florbetapir) individuals were different.…”

Distinct and joint effects of low and high levels of Aβ and tau deposition on cortical thickness

“…According to our hypothesis, when the effects of Aβ and tau overlap and synergize, the resonance between the two pathologies can be detected by assessing the spatial similarity between their pattern of accumulation throughout the entire cerebral cortex, which eventually can lead to cognitive decline. This hypothesis is supported by significant basic science work showing that the combination of Aβ and tau that leads to neurodegeneration via mechanisms including microglial activation, synaptic spine loss, and suppression of neuronal activity, while either protein in isolation is often compatible with normal functioning ( Busche and Hyman, 2020 , Koller, 2021 ).…”