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 sequestration of disease-specific proteins in the brain, but the events that initiate this process remain unclear. To determine whether the deposition of the beta-amyloid peptide (Abeta), 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 beta-amyloid precursor protein (betaAPP)-transgenic mice. Up to 4 weeks after the infusion there was no Abeta-deposition in the brain; however, after 5 months, the AD-tissue-injected hemisphere of the transgenic mice had developed profuse Abeta-immunoreactive senile plaques and vascular deposits, some of which were birefringent with Congo Red. There was limited deposition of diffuse Abeta also in the brains of betaAPP-transgenic mice infused with tissue from an age-matched, non-AD brain with mild beta-amyloidosis, but none in mice receiving extract from a young control case. Abeta deposits also were not found in either 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 pathogenic commonality between beta-amyloidosis and other neurodegenerative diseases involving abnormal protein polymerization. The paradigm can be used to clarify the conditions that initiate in vivo beta-amyloidogenesis in the brain and may yield a more authentic animal model of Alzheimer's disease and other neurodegenerative disorders.
Kane
M D
MD
Neuroscience Therapeutics, Parke-Davis Research, Division of Warner-Lambert, Ann Arbor, Michigan 48105, USA.
Lipinski
W J
WJ
Callahan
M J
MJ
Bian
F
F
Durham
R A
RA
Schwarz
R D
RD
Roher
A E
AE
Walker
L C
LC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000937:Antigen-Antibody Reactions; D002536:Cerebral Arteries / Q000473:pathology; D004396:Coloring Agents; D003224:Congo Red; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004396:Coloring Agents; D003224:Congo Red