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Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline.
J Neurosci. 2010 May 26; 30(21):7281-9.JN

Abstract

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.

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Authors+Show Affiliations

Clinton LK
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4545, USA.
Blurton-Jones M
No affiliation info available
Myczek K
No affiliation info available
Trojanowski JQ
No affiliation info available
LaFerla FM
No affiliation info available

MeSH

Age FactorsAlzheimer DiseaseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAnimalsAvoidance LearningBrainCognition DisordersDisease Models, AnimalGene Expression Regulation, DevelopmentalHumansInhibition, PsychologicalLewy BodiesMaze LearningMiceMice, Inbred C57BLMice, TransgenicMotor ActivityMutationPhosphorylationPresenilin-1alpha-Synucleintau Proteins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20505094

Citation

Clinton, Lani K., et al. "Synergistic Interactions Between Abeta, Tau, and Alpha-synuclein: Acceleration of Neuropathology and Cognitive Decline." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 30, no. 21, 2010, pp. 7281-9.
Clinton LK, Blurton-Jones M, Myczek K, et al. Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010;30(21):7281-9.
Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q., & LaFerla, F. M. (2010). Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 30(21), 7281-9. https://doi.org/10.1523/JNEUROSCI.0490-10.2010
Clinton LK, et al. Synergistic Interactions Between Abeta, Tau, and Alpha-synuclein: Acceleration of Neuropathology and Cognitive Decline. J Neurosci. 2010 May 26;30(21):7281-9. PubMed PMID: 20505094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. AU - Clinton,Lani K, AU - Blurton-Jones,Mathew, AU - Myczek,Kristoffer, AU - Trojanowski,John Q, AU - LaFerla,Frank M, PY - 2010/5/28/entrez PY - 2010/5/28/pubmed PY - 2010/6/16/medline SP - 7281 EP - 9 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 30 IS - 21 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/20505094/Synergistic_Interactions_between_Abeta_tau_and_alpha_synuclein:_acceleration_of_neuropathology_and_cognitive_decline_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=20505094 DB - PRIME DP - Unbound Medicine ER -