Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.
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 in patients 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.-Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., Jicha, G. A., Karydas, A. M., Boxer, A., Miller, B. L. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.
Department of Medicine, University of California, San Francisco, San Francisco, California, USA; edward.goetzl@ucsf.edu.|Jewish Home of San Francisco, San Francisco, California, USA.
Edward J
EJ
Goetzl
Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland, USA.
Dimitrios
D
Kapogiannis
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Jewish Home of San Francisco, San Francisco, California, USA.|Department of Bioengineering, University of California, San Francisco, San Francisco, California, USA.
Janice B
JB
Schwartz
Clinical Translational Science Institute, University of California, San Francisco, San Francisco, California, USA.
Iryna V
IV
Lobach
Department of Obstetrics, Gynecology, and Reproductive Sciences, Temple University, Philadelphia, Pennsylvania, USA.
Laura
L
Goetzl
Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
Erin L
EL
Abner
Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
Gregory A
GA
Jicha
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Anna M
AM
Karydas
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Adam
A
Boxer
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Bruce L
BL
Miller
D000544:Alzheimer Disease / Q000097:blood / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D003071:Cognition / Q000502:physiology; D003430:Cross-Sectional Studies; D055354:Exosomes / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000097:blood / Q000175:diagnosis*; D006801:Humans; D008137:Longitudinal Studies; D013569:Synapses / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016875:tau Proteins
biomarkers; cognition; neurotransmission; proteinopathy