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The Complex PrPc-Fyn Couples Human Oligomeric Aβ with Pathological Tau Changes in Alzheimer's Disease

Larson, Megan; Sherman, Mathew A; Amar, Fatou; Nuvolone, Mario; Schneider, Julie A; Bennett, David A; Aguzzi, Adriano; Lesné, Sylvain E (2012). The Complex PrPc-Fyn Couples Human Oligomeric Aβ with Pathological Tau Changes in Alzheimer's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32(47):16857-16871.

Abstract

Amid controversy, the cellular form of the prion protein PrP(c) has been proposed to mediate oligomeric amyloid-β (Aβ)-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by Aβ oligomers and leads to synaptic and cognitive impairment in transgenic animals. However, the molecular mechanism by which soluble Aβ activates Fyn remains unknown. Combining the use of human and transgenic mouse brain tissue as well as primary cortical neurons, we demonstrate that soluble Aβ binds to PrP(c) at neuronal dendritic spines in vivo and in vitro where it forms a complex with Fyn, resulting in the activation of the kinase. Using the antibody 6D11 to prevent oligomeric Aβ from binding to PrP(c), we abolished Fyn activation and Fyn-dependent tau hyperphosphorylation induced by endogenous oligomeric Aβ in vitro. Finally, we showed that gene dosage of Prnp regulates Aβ-induced Fyn/tau alterations. Together, our findings identify a complete signaling cascade linking one specific endogenous Aβ oligomer, Fyn alteration, and tau hyperphosphorylation in cellular and animal models modeling aspects of the molecular pathogenesis of Alzheimer's disease.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Neuroscience
Language:English
Date:2012
Deposited On:30 Nov 2012 12:51
Last Modified:08 Nov 2024 02:36
Publisher:Society for Neuroscience
Series Name:Journal of Neuroscience
ISSN:0270-6474
OA Status:Closed
Publisher DOI:https://doi.org/10.1523/JNEUROSCI.1858-12.2012
PubMed ID:23175838

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