Abstract
OBJECTIVE: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy.
METHODS: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker.
RESULTS: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p ≤ 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p ≤ 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p ≤ 0.0003).
CONCLUSIONS: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies.
Document Type
Article
Publication Date
7-7-2015
Digital Object Identifier (DOI)
http://dx.doi.org/10.1212/WNL.0000000000001702
Funding Information
Intramural Research Program of the National Institute on Aging (NIA; D.K.), UK ADC P30, AG028383 (E.L.A.), and an unrestricted grant for method development from NanoSomiX, Inc. (E.J.G.).
Repository Citation
Goetzl, Edward J.; Boxer, Adam; Schwartz, Janice B.; Abner, Erin L.; Petersen, Ronald C.; Miller, Bruce L.; and Kapogiannis, Dimitrios, "Altered Lysosomal Proteins in Neural-Derived Plasma Exosomes in Preclinical Alzheimer Disease" (2015). Sanders-Brown Center on Aging Faculty Publications. 45.
https://uknowledge.uky.edu/sbcoa_facpub/45
Figures 1 & 2
Figure_e-1.pdf (13 kB)
Figure e-1
Table_e-1.docx (20 kB)
Table e-1
Notes/Citation Information
Published in Neurology, v. 85, no. 1, p. 40-47.
© 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
The copyright holders have granted the permission for posting the article here.