Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease

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.

© 2015 American Academy of Neurology.

Figures

Figure 1. Levels of plasma exosomal proteins in patients with AD, FTD, and cognitively normal case controls

The horizontal line in each cluster here and in figure 2 depicts the mean for that set. AC = Alzheimer normal control; AD = Alzheimer disease; FTC = frontotemporal normal control; FTD = frontotemporal dementia; HSP70 = heat-shock protein 70; LAMP-1 = lysosome-associated membrane protein 1.

Figure 2. Sequential levels of plasma exosomal proteins in patients with AD measured first at a time of normal cognition (preclinical, AP) and later at the time of development of aMCI or dementia (AD), as contrasted with cognitively normal control participants (AC) matched to individuals in their preclinical phase

AC = Alzheimer normal control; AD = Alzheimer disease; aMCI = amnestic mild cognitive impairment; AP = preclinical Alzheimer disease; FTC = frontotemporal normal control; FTD = frontotemporal dementia; HSP70 = heat-shock protein 70; LAMP-1 = lysosome-associated membrane protein 1.