Experimental evidence that readily diffusible forms of Aβ from Alzheimer’s disease brain have seeding activity

Significant data suggest that cerebral accumulation of the amyloid β-protein (Aβ) plays an initiating role in Alzheimer's disease (AD), however, Aβ can exist in multiple different forms and it is not clear which of these contribute to the propagation of amyloid or toxicity. When injected into animal models, Aβ-containing homogenates from AD or APP transgenic mouse brain accelerate amyloid pathology, but the nature of the seeding species remain ill-defined. In this study, we took advantage of well-characterized brain extracts from human AD cases and App^NL-F/NL-F mice, to assess the seeding activity of diffusible forms of Aβ. Extracts containing readily diffusible forms of Aβ, (which we refer to as S extracts) are obtained by soaking tissue slices in physiological buffer and removing large non-diffusing material by centrifugation. Such AD brain S extracts are potent neuritotoxins and contain a broad range of different sized forms Aβ. When tested at approximately ten months after a single intracerebral injection of AD brain S extract, App^NL-F/NL-F mice exhibited a significant perturbation of learned behavior, together with accelerated cerebral amyloid deposition, microgliosis, astrocytosis, neuronal dystrophy and synaptic loss. Importantly, inoculation of App^NL-F/NL-F mice with S extract from a human control brain altered neither the memory of learned behavior nor the appearance of amyloid and associated pathologies. These results indicate that diffusible forms of Aβ derived from AD brain can readily induce aggregation of endogenous Aβ and accelerate negative outcomes associated with Aβ accumulation.