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

Aims To illuminate the pathological synergy between A beta 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 A beta 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 A beta (pre-deposit cohort) or with frank A beta deposits (post-deposit cohort). Results Expression of WT tau did not produce NFT or altered A beta in either cohort. In the pre-deposit cohort, S320F tau induced A beta 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 A beta-tau synergy based on the nature of A beta. P301L tau produced NFT-type inclusions in the post-deposit cohort, but not in the pre-deposit cohort, indicating pathological synergy with pre-existing A beta deposits. Conclusions Our data show that different tau mutations representing specific folding variants of tau synergise with A beta to different extents, depending on the presence of cerebral deposits.