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Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology.
Neuron. 2020 01 22; 105(2):260-275.e6.N

Abstract

Studies have shown an overlap of Aβ plaques, tau tangles, and α-synuclein (α-syn) pathologies in the brains of Alzheimer's disease (AD) and Parkinson's disease (PD) with dementia (PDD) patients, with increased pathological burden correlating with severity of cognitive and motor symptoms. Despite the observed co-pathology and concomitance of motor and cognitive phenotypes, the consequences of the primary amyloidogenic protein on the secondary pathologies remain poorly understood. To better define the relationship between α-syn and Aβ plaques, we injected α-syn preformed fibrils (α-syn mpffs) into mice with abundant Aβ plaques. Aβ deposits dramatically accelerated α-syn pathogenesis and spread throughout the brain. Remarkably, hyperphosphorylated tau (p-tau) was induced in α-syn mpff-injected 5xFAD mice. Finally, α-syn mpff-injected 5xFAD mice showed neuron loss that correlated with the progressive decline of cognitive and motor performance. Our findings suggest a "feed-forward" mechanism whereby Aβ plaques enhance endogenous α-syn seeding and spreading over time post-injection with mpffs.

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Authors+Show Affiliations

Bassil F
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Brown HJ
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Pattabhiraman S
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Iwasyk JE
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Maghames CM
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Meymand ES
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cox TO
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Riddle DM
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Zhang B
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Trojanowski JQ
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Lee VM
The Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: vmylee@upenn.edu.

MeSH

AnimalsBrainCell CountCognitive DysfunctionHumansLewy Body DiseaseMiceMotor ActivityNeuronsPhosphorylationPlaque, Amyloidalpha-Synucleintau Proteins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31759806

Citation

Bassil, Fares, et al. "Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders With Aβ Pathology." Neuron, vol. 105, no. 2, 2020, pp. 260-275.e6.
Bassil F, Brown HJ, Pattabhiraman S, et al. Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology. Neuron. 2020;105(2):260-275.e6.
Bassil, F., Brown, H. J., Pattabhiraman, S., Iwasyk, J. E., Maghames, C. M., Meymand, E. S., Cox, T. O., Riddle, D. M., Zhang, B., Trojanowski, J. Q., & Lee, V. M. (2020). Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology. Neuron, 105(2), 260-e6. https://doi.org/10.1016/j.neuron.2019.10.010
Bassil F, et al. Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders With Aβ Pathology. Neuron. 2020 01 22;105(2):260-275.e6. PubMed PMID: 31759806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology. AU - Bassil,Fares, AU - Brown,Hannah J, AU - Pattabhiraman,Shankar, AU - Iwasyk,Joe E, AU - Maghames,Chantal M, AU - Meymand,Emily S, AU - Cox,Timothy O, AU - Riddle,Dawn M, AU - Zhang,Bin, AU - Trojanowski,John Q, AU - Lee,Virginia M-Y, Y1 - 2019/11/20/ PY - 2019/04/02/received PY - 2019/08/12/revised PY - 2019/10/03/accepted PY - 2019/11/25/pubmed PY - 2020/3/31/medline PY - 2019/11/25/entrez KW - Lewy bodies KW - Parkinson’s disease KW - alpha-synuclein KW - alzheimer's disease KW - amyloid-beta plaques KW - comorbidity KW - dementia KW - parkinsonism KW - tau SP - 260 EP - 275.e6 JF - Neuron JO - Neuron VL - 105 IS - 2 N2 - Studies have shown an overlap of Aβ plaques, tau tangles, and α-synuclein (α-syn) pathologies in the brains of Alzheimer's disease (AD) and Parkinson's disease (PD) with dementia (PDD) patients, with increased pathological burden correlating with severity of cognitive and motor symptoms. Despite the observed co-pathology and concomitance of motor and cognitive phenotypes, the consequences of the primary amyloidogenic protein on the secondary pathologies remain poorly understood. To better define the relationship between α-syn and Aβ plaques, we injected α-syn preformed fibrils (α-syn mpffs) into mice with abundant Aβ plaques. Aβ deposits dramatically accelerated α-syn pathogenesis and spread throughout the brain. Remarkably, hyperphosphorylated tau (p-tau) was induced in α-syn mpff-injected 5xFAD mice. Finally, α-syn mpff-injected 5xFAD mice showed neuron loss that correlated with the progressive decline of cognitive and motor performance. Our findings suggest a "feed-forward" mechanism whereby Aβ plaques enhance endogenous α-syn seeding and spreading over time post-injection with mpffs. SN - 1097-4199 UR - https://www.unboundmedicine.com/medline/citation/31759806/Amyloid_Beta__Aβ__Plaques_Promote_Seeding_and_Spreading_of_Alpha_Synuclein_and_Tau_in_a_Mouse_Model_of_Lewy_Body_Disorders_with_Aβ_Pathology_ DB - PRIME DP - Unbound Medicine ER -