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The Journal of Neuroscience, May 15, 2000, 20(10):3606-3611

Evidence for Seeding of -Amyloid by Intracerebral Infusion of Alzheimer Brain Extracts in -Amyloid Precursor Protein-Transgenic Mice

Michael D. Kane¹, William J. Lipinski¹, Michael J. Callahan¹, Feng Bian¹, Robert A. Durham¹, Roy D. Schwarz¹, Alex E. Roher², and Lary C. Walker¹

¹ Neuroscience Therapeutics, Parke-Davis Research, Division of Warner-Lambert, Ann Arbor, Michigan 48105, and ² Haldeman Laboratory for Alzheimer's Disease Research, Sun Health Research Institute, Sun City, Arizona 85372

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 -amyloid peptide (A), 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 -amyloid precursor protein (APP)-transgenic mice. Up to 4 weeks after the infusion there was no A-deposition in the brain; however, after 5 months, the AD-tissue-injected hemisphere of the transgenic mice had developed profuse A-immunoreactive senile plaques and vascular deposits, some of which were birefringent with Congo Red. There was limited deposition of diffuse A also in the brains of APP-transgenic mice infused with tissue from an age-matched, non-AD brain with mild -amyloidosis, but none in mice receiving extract from a young control case. A deposits also were not found in either vehicle-injected or uninjected transgenic mice or in any nontransgenic mice. The results show that cerebral -amyloid can be seeded in vivo by a single inoculation of dilute AD brain extract, demonstrating a key pathogenic commonality between -amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo -amyloidogenesis in the brain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.

Key words: Alzheimer's disease; amyloid; angiopathy; A; transgenic; prion; seeding; neurodegeneration; neuroinflammation; animal model; conformational disease

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20103606-06$05.00/0

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