Despite the importance of the aberrant polymerization of A␤ in the early pathogenic cascade of Alzheimer's disease, little is known about the induction of A␤ aggregation in vivo. Here we show that induction of cerebral ␤-amyloidosis can be achieved in many different brain areas of APP23 transgenic mice through the injection of dilute A␤-containing brain extracts. Once the amyloidogenic process has been exogenously induced, the nature of the induced A␤-deposition is determined by the brain region of the host. Because these observations are reminiscent of a prion-like mechanism, we then investigated whether cerebral ␤-amyloidosis also can be induced by peripheral and systemic inoculations or by the intracerebral implantation of stainless steel wires previously coated with minute amounts of A␤-containing brain extract. Results reveal that oral, intravenous, intraocular, and intranasal inoculations yielded no detectable induction of cerebral ␤-amyloidosis in APP23 transgenic mice. In contrast, transmission of cerebral ␤-amyloidosis through the A␤-contaminated steel wires was demonstrated. Notably, plasma sterilization, but not boiling of the wires before implantation, prevented the induction of ␤-amyloidosis. Our results suggest that minute amounts of A␤-containing brain material in direct contact with the CNS can induce cerebral ␤-amyloidosis, but that systemic cellular mechanisms of prion uptake and transport to the CNS may not apply to A␤.Alzheimer's disease ͉ amyloid ͉ prion ͉ sterilization ͉ transmission

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

The polymorphic b-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral b-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop b-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and Ab40/Ab42 peptide ratio. To determine the nature of such b-amyloid morphotypes, b-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced b-amyloid deposition with the morphological, conformational, and Ab40/Ab42 ratio characteristics of b-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of b-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced b-amyloid deposits, although less prominent, and the induced deposits were similar to the b-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated Ab in APP transgenic mice can be maintained by seeded conversion.