Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer's disease and mild cognitive impairment

Abstract

Dementia is a neurocognitive disorder characterized by a progressive memory loss and impairment in cognitive and functional abilities. Autophagy and mitophagy are two important cellular processes by which the damaged intracellular components are degraded by lysosomes. To investigate the contribution of autophagy and mitophagy in degenerative diseases, we investigated the serum levels of specific autophagic markers (ATG5 protein) and mitophagic markers (Parkin protein) in a population of older patients by enzyme-linked immunosorbent assay. Two hundred elderly (≥65 years) outpatients were included in the study: 40 (20 F and 20 M) with mild-moderate late onset Alzheimer's disease (AD); 40 (20 F and 20 M) affected by vascular dementia (VAD); 40 with mild cognitive impairment (MCI); 40 (20 F and 20 M) with "mixed" dementia (MD); 40 subjects without signs of cognitive impairment were included as sex-matched controls. Our data indicated that, in serum samples, ATG5 and Parkin were both elevated in controls, and that VAD compared with AD, MCI and MD (all p < 0.01). Patients affected by AD, MD, and MCI showed significantly reduced circulating levels of both ATG5 and Parkin compared to healthy controls and VAD individuals, reflecting a significant down-regulation of autophagy and mitophagy pathways in these groups of patients. The measurement of serum levels of ATG5 and Parkin may represent an easily accessible diagnostic tool for the early monitoring of patients with cognitive decline.

Figure 1

Serum levels of ATG5 and Parkin in sera of patients affected by Alzheimer’s disease (AD), vascular dementia (VAD), mild cognitive impairment (MCI), “mixed” dementia (MD) and without signs of cognitive impairment as sex-matched controls. Panel A: ATG5 levels were different among groups (Kruskall-Wallis; p < 0.0001), in particular in post hoc analysis (Dunn’s post hoc test) median ATG5 values were more elevated in Controls and VAD than in AD (p = 0.0051 and p < 0.0001), MCI (p = 0.0004 and p < 0.0001) and MD (p = 0.0045 and p < 0.0001). Panel B: Parkin levels were different among groups (Kruskall-Wallis; p < 0.0001), post hoc analysis (Dunn’s post hoc test) showed higher median values in Controls and VAD respect to AD (p = 0.0034 and p = 0.0029), MCI (both p < 0.0001) and MD (both p = 0.0001). *After stratification by sex, ATG5 and Parkin value resulted augmented in males compared to females in VAD subgroup (Mann-Whitney; p < 0.0001 and p = 0.0245, respectively). The boundaries of the boxes represent the 25th–75th quartile. The line within the box indicates the median. The vertical lines above and below the box correspond to the highest and lowest values.