Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline.
Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorder, is characterized pathologically by the accumulation of beta-amyloid (Abeta) plaques and tau-laden neurofibrillary tangles. Interestingly, up to 50% of AD cases exhibit a third prevalent neuropathology: the aggregation of alpha-synuclein into Lewy bodies. Importantly, the presence of Lewy body pathology in AD is associated with a more aggressive disease course and accelerated cognitive dysfunction. Thus, Abeta, tau, and alpha-synuclein may interact synergistically to promote the accumulation of each other. In this study, we used a genetic approach to generate a model that exhibits the combined pathologies of AD and dementia with Lewy bodies (DLB). To achieve this goal, we introduced a mutant human alpha-synuclein transgene into 3xTg-AD mice. As occurs in human disease, transgenic mice that develop both DLB and AD pathologies (DLB-AD mice) exhibit accelerated cognitive decline associated with a dramatic enhancement of Abeta, tau, and alpha-synuclein pathologies. Our findings also provide additional evidence that the accumulation of alpha-synuclein alone can significantly disrupt cognition. Together, our data support the notion that Abeta, tau, and alpha-synuclein interact in vivo to promote the aggregation and accumulation of each other and accelerate cognitive dysfunction.
Clinton
Lani K
LK
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4545, USA.
Blurton-Jones
Mathew
M
Myczek
Kristoffer
K
Trojanowski
John Q
JQ
LaFerla
Frank M
FM
D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007266:Inhibition, Psychological; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051844:alpha-Synuclein; D016875:tau Proteins