Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease

Edward J. Goetzl, Dimitrios Kapogiannis, Janice B. Schwartz, Iryna V. Lobach, Laura Goetzl, Erin L. Abner, Gregory A. Jicha, Anna M. Karydas, Adam Boxer, Bruce L. Miller

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291 Scopus citations

Abstract

Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia inpatients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid β-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias.

Original languageEnglish
Pages (from-to)4141-4148
Number of pages8
JournalFASEB Journal
Volume30
Issue number12
DOIs
StatePublished - Dec 2016

Bibliographical note

Publisher Copyright:
© 2016 FASEB.

Funding

The authors thank Sonya Anderson (University of Kentucky Alzheimer's Disease Center) for organizing and distributing biospecimens and Judith H. Goetzl (Jewish Home of San Francisco) for expert production of graphic illustrations. This work was supported by a grant from the BAND2 Program of the Michael J. Fox Foundation for Parkinson's Research, the Alzheimer's Association, Alzheimer's Research UK, and the Weston Brain Institute (Toronto, ON, Canada), by a grant for methodological development from Nanosomix (to E.J.G.), the Intramural Program of the U.S. National Institutes of Health, National Institute on Aging (NIA; to D.K.), and NIA Grant P30 AG028383 (to E.L.A.). E.J.G. has filed an application with the U.S. Patent Office for the platform and methodologies described in this report; he is a founder of Nanosomix, but now receives no salary or consulting fees, but only support for laboratory supplies. E.L.A. received travel support from Nanosomix for the 2015 annual meeting of the American Association for the Advancement of Science. A.B. declares that outside the submitted studies, he has grants from the NIA, Tau Research Consortium, Allon Therapeutics, Genentech, Bristol-Myers Squibb, TauRx, Alzheimer's Association, Bluefield Project to Cure FTD, the Association for Frontotemporal Degeneration, Alzheimer's Drug Discovery Foundation, EnVivo, C2N Diagnostics, Pfizer, Eli Lilly, and Corticobasal Degeneration Solutions; grants, personal fees, and nonfinancial support from Archer Biosciences; personal fees from Acetylon; and personal fees from iPierian. The remaining authors declare no conflicts of interest.

FundersFunder number
Tau Research Consortium
TauRX Therapeutics Ltd
University of Kentucky Alzheimer's Disease research center
National Institutes of Health (NIH)
National Institute on AgingP30AG028383
Alzheimer's Association
American Association for the Advancement of Science
Bristol-Myers Squibb
Alzheimer's Drug Discovery Foundation
Association for Frontotemporal Degeneration
Eli Lilly and Company
Genentech Incorporated
Allos Therapeutics
Weston Brain Institute
Bristol Research into Alzheimer’s and Care of the Elderly

    Keywords

    • Biomarkers
    • Cognition
    • Neurotransmission
    • Proteinopathy

    ASJC Scopus subject areas

    • Biotechnology
    • Biochemistry
    • Molecular Biology
    • Genetics

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