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

Abstract

Many neurodegenerative diseases are associated with the abnormal sequestration of disease-specific proteins in the brain, but the events that initiate this process remain unclear. To determine whether the deposition of the β-amyloid peptide (Aβ), a key pathological feature of Alzheimer's disease (AD), can be induced in vivo, we infused dilute supernatants of autopsy-derived neocortical homogenates from Alzheimer's patients unilaterally into the hippocampus and neocortex of 3-month-old β-amyloid precursor protein (βAPP)-transgenic mice. Up to 4 weeks after the infusion there was no Aβ-deposition in the brain; however, after 5 months, the AD- tissue-injected hemisphere of the transgenic mice had developed profuse Aβ- immunoreactive senile plaques and vascular deposits, some of which were birefringent with Congo Red. There was limited deposition of diffuse Aβ also in the brains of βAPP-transgenic mice infused with tissue from an age- matched, non-AD brain with mild β-amyloidosis, but none in mice receiving extract from a young control case. Aβ deposits also were not found in either vehicle-injected or uninjected transgenic mice or in any nontransgenic mice. The results show that cerebral β-amyloid can be seeded in vivo by a single inoculation of dilute AD brain extract, demonstrating a key pathogenic commonality between β-amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo β-amyloidogenesis in the brain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.