Evidence for seeding of beta-amyloid by intracerebral infusion of Alzheimer brain extracts in beta-amyloid precursor protein-transgenic mice

Many neurodegenerative diseases are associated with the abnormal sequestrat ion of disease-specific proteins in the brain, but the events that initiate this process remain unclear. To determine whether the deposition of the be ta-amyloid peptide (A beta), a key pathological feature of Alzheimer's dise ase (AD), can be induced in vivo, we infused dilute supernatants of autopsy -derived neocortical homogenates from Alzheimer's patients unilaterally int o the hippocampus and neocortex of 3-month-old beta-amyloid precursor prote in (beta APP)-transgenic mice. Up to 4 weeks after the infusion there was n o A beta-deposition in the brain; however, after 5 months, the AD-tissue-in jected hemisphere of the transgenic mice had developed profuse A beta-immun oreactive senile plaques and vascular deposits, some of which were birefrin gent with Congo Red. There was limited deposition of diffuse A beta also in the brains of beta APP-transgenic mice infused with tissue from an age-mat ched, non-AD brain with mild beta-amyloidosis, but none in mice receiving e xtract from a young control case. A beta deposits also were not found in ei ther vehicle-injected or uninjected transgenic mice or in any nontransgenic mice. The results show that cerebral beta-amyloid can be seeded in vivo by a single inoculation of dilute AD brain extract, demonstrating a key patho genic commonality between beta-amyloidosis and other neurodegenerative dise ases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo beta-amyloidogenesis in the b rain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.