Induction and characterisation of Aβ and tau pathology in App ^NL-F/NL-F mice following inoculation with Alzheimer’s disease brain homogenate

Alzheimer’s disease (AD) is defined by the accumulation of neurofibrillary tangles containing hyperphosphorylated Tau and plaques containing Amyloid-β (Aβ). The aggregation of these two proteins is considered central to the disease. The lack of animal models that can recapitulate Aβ and tau pathologies without overexpressing these proteins has hindered AD research. Accelerating pathology by inoculating Aβ and tau seeds has helped to understand their prion-like propagation in the brain. Previous studies failed to characterise both Aβ and tau pathologies in vivo upon inoculating AD brain homogenates. Here we present a longitudinal and systematic study; we inoculated the App ^NL-F/NL-F knockin mice, which express humanised Aβ and murine wild-type tau, with extracts from diseased human brains to analyse the contribution of Aβ and tau assemblies to AD pathogenesis. We found that mice inoculated with AD brain extracts evinced early and prominent amyloid deposition, while those injected with control brain extracts or vehicle did not. Parenchymal and vascular amyloid accumulated in the same brain regions affected in control-inoculated App ^NL-F/NL-F mice. However, the extent of vascular amyloid far exceeded that seen in App ^NL-F/NL-F mice injected with control brain extracts, and parenchymal deposits extended to a previously untargeted brain region – the cerebellum. An end-point titration of an AD brain homogenate in App ^NL-F/NL-F mice demonstrated that human Aβ seeds can be titrated in a prion-like fashion, which is useful for sample comparison, diagnostic and risk studies. Notably, the inoculation of App ^NL-F/NL-F mice with AD brain homogenate induced intense tau phosphorylation, and provides more detailed context for the inoculation of App ^NL-F/NL-F mice with human samples to study temporal and mechanistic relationships between Aβ and tau pathology, vascular amyloid deposition and bioactivity of Aβ seeds.