Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease.
Amyloid-beta (Abeta) containing plaques and tau-laden neurofibrillary tangles are the defining neuropathological features of Alzheimer's disease (AD). To better mimic this neuropathology, we generated a novel triple transgenic model of AD (3xTg-AD) harboring three mutant genes: beta-amyloid precursor protein (betaAPPSwe), presenilin-1 (PS1M146V), and tauP301L. The 3xTg-AD mice progressively develop Abeta and tau pathology, with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We find that Abeta deposits initiate in the cortex and progress to the hippocampus with aging, whereas tau pathology is first apparent in the hippocampus and then progresses to the cortex. Despite equivalent overexpression of the human betaAPP and human tau transgenes, Abeta deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated.
Oddo
Salvatore
S
Department of Neurobiology and Behavior, University of California, 1109 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4545, USA.
Caccamo
Antonella
A
Kitazawa
Masashi
M
Tseng
Bertrand P
BP
LaFerla
Frank M
FM
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1; D016875:tau Proteins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins