Soluble Aβ Seeds Are Potent Inducers of Cerebral β-Amyloid Deposition

Cerebral beta-amyloidosis and associated pathologies can be exogenously induced by the intracerebral injection of small amounts of pathogenic A beta-containing brain extract into young beta-amyloid precursor protein (APP) transgenic mice. The probable beta-amyloid-inducing factor in the brain extract has been identified as a species of aggregated A beta that is generated in its most effective conformation or composition in vivo. Here we report that A beta in the brain extract is more proteinase K (PK) resistant than is synthetic fibrillar A beta, and that this PK-resistant fraction of the brain extract retains the capacity to induce beta-amyloid deposition upon intracerebral injection in young, pre-depositing APP23 transgenic mice. After ultracentrifugation of the brain extract, <0.05% of the A beta remained in the supernatant fraction, and these soluble A beta species were largely PK sensitive. However, upon intracerebral injection, this soluble fraction accounted for up to 30% of the beta-amyloid induction observed with the unfractionated extract. Fragmentation of the A beta seeds by extended sonication increased the seeding capacity of the brain extract. In summary, these results suggest that multiple A beta assemblies, with various PK sensitivities, are capable of inducing beta-amyloid aggregation in vivo. The finding that small and soluble A beta seeds are potent inducers of cerebral beta-amyloidosis raises the possibility that such seeds may mediate the spread of beta-amyloidosis in the brain. If they can be identified in vivo, soluble A beta seeds in bodily fluids also could serve as early biomarkers for cerebral beta-amyloidogenesis and eventually Alzheimer's disease.