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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 (Cambridge, Mass.), 2020-01, Vol.105 (2), p.260-275.e6 [Peer Reviewed Journal]

2019 Elsevier Inc. ;Copyright © 2019 Elsevier Inc. All rights reserved. ;2019. Elsevier Inc. ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2019.10.010 ;PMID: 31759806

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Title:
Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading of Alpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology
Author: Bassil, Fares ; Brown, Hannah J. ; Pattabhiraman, Shankar ; Iwasyk, Joe E. ; Maghames, Chantal M. ; Meymand, Emily S. ; Cox, Timothy O. ; Riddle, Dawn M. ; Zhang, Bin ; Trojanowski, John Q. ; Lee, Virginia M.-Y.
Subjects: alpha-synuclein ; alpha-Synuclein - administration & dosage ; alpha-Synuclein - metabolism ; Alzheimer's disease ; amyloid-beta plaques ; Amyloidogenesis ; Animals ; Brain ; Brain - metabolism ; Cell Count ; Cognitive ability ; Cognitive Dysfunction - pathology ; comorbidity ; Dementia ; Dementia disorders ; Fibrils ; Humans ; Lewy bodies ; Lewy Body Disease - metabolism ; Lewy Body Disease - pathology ; Mice ; Motor Activity ; Motor task performance ; Movement disorders ; Neurodegenerative diseases ; Neurons - pathology ; Parkinson's disease ; parkinsonism ; Pathology ; Phenotypes ; Phosphorylation ; Plaque, Amyloid - metabolism ; Plaques ; Protein seeding ; Rodents ; Spreading ; Synuclein ; tau ; Tau protein ; tau Proteins - metabolism
Is Part Of: Neuron (Cambridge, Mass.), 2020-01, Vol.105 (2), p.260-275.e6
Description: 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. •α-syn burden is associated with Aβ plaque load in the cortex of LBD patients•Aβ plaques potentiate α-syn spreading in 5xFAD mice•Aβ plaques establish a dynamic pre-misfolded pool of α-syn in dystrophic neurites•Aβ/α-syn co-pathology induces neurodegeneration and behavioral deficits Bassil et al. describe a new model that shows how Aβ plaques in the brain can potentiate α-synuclein pathogenesis. The authors provide evidence that the interaction of both proteins in the brain lead to neurodegeneration.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0896-6273
EISSN: 1097-4199
DOI: 10.1016/j.neuron.2019.10.010
PMID: 31759806
Source: MEDLINE
Open Access: Cell Press Free Archives

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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

2019 Elsevier Inc. ;Copyright © 2019 Elsevier Inc. All rights reserved. ;2019. Elsevier Inc. ;ISSN: 0896-6273 ;EISSN: 1097-4199 ;DOI: 10.1016/j.neuron.2019.10.010 ;PMID: 31759806

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