α-Synuclein Aggregated with Tau and β-Amyloid in Human Platelets from Healthy Subjects: Correlation with Physical Exercise

Abstract

The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids. In this respect, we have demonstrated that α-syn forms detectable hetero-aggregates with Aβ or tau in red blood cells (RBCs) of healthy subjects. In particular, α-syn levels and its heteromeric interactions are modulated by plasma antioxidant capability (AOC), which increases in turn with physical activity. In order to understand if a specific distribution of misfolded proteins can occur in other blood cells, a cohort of human subjects was enrolled to establish a correlation among AOC, the level of physical exercise and the concentrations of aging-related proteins in platelets. The healthy subjects were divided depending on their level of physical exercise (i.e., athletes and sedentary subjects) and their age (young and older subjects). Herein, aging-related proteins (i.e., α-syn, tau and Aβ) were confirmed to be present in human platelets. Among such proteins, platelet tau concentration was demonstrated to decrease in athletes, while α-syn and Aβ did not correlate with physical exercise. For the first time, α-syn was shown to directly interact with Aβ and tau in platelets, forming detectable hetero-complexes. Interestingly, α-syn interaction with tau was inversely related to plasma AOC and to the level of physical activity. These results suggested that α-syn heterocomplexes, particularly with tau, could represent novel indicators to monitor aging-related proteins in platelets.

α-Synuclein Heterocomplexes with β-Amyloid Are Increased in Red Blood Cells of Parkinson’s Disease Patients and Correlate with Disease Severity

“…Co-immunoprecipitation analysis qualitatively showed that α-syn associated with Aβ 1–42 and tau in RBCs from HC and PD patients (Figure 3A and Supplementary Figure S2). Such results are consistent with those obtained in RBCs (Daniele et al, 2017 ) and platelets (Daniele et al, 2018 ) of HC and confirm the existence of hybrid oligomers at peripheral level.…”

Epigenetic Modifications of the α‐Synuclein Gene and Relative Protein Content Are Affected by Ageing and Physical Exercise in Blood from Healthy Subjects

“…Older subjects presented lower levels of total but not oligomeric α -syn. Similar data on the protein levels were reported in RBCs, plasma, or platelets of healthy subjects or PD patients [ 62 – 66 ]. Moreover, a significant inverse correlation with age in the selected population presenting RBC α -syn concentrations up to 76.3 ng/mg protein (confidence interval = 95%) was observed.…”

“…These data suggest that hypermethylation of intron1- SNCA can lead to a lower concentration of total α -syn in the blood, at least for a population presenting up to 76.3 ng/mg protein. In fact, the current hypothesis is that the minor levels presented by an elderly population or PD patients are the result of protein sequestration into oligomeric forms [ 62 – 66 ]. Further investigations are needed to clarify the effective influence of SNCA methylation on α -syn accumulation in the peripheral cells.…”

α-Synuclein heteromers with ß-amyloid and tau decreased in red blood cells of Alzheimer’s disease and Lewy Body dementia patients.

“…Heterocomplexes of α-syn with tau and Aβ 1−42 have been proven to occur both in cellular models and in patients' brains [21-24, 34, 35, 71]. Noteworthy, α-syn forms heterocomplexes with both Aβ 1−42 and tau proteins in brain tissues and RBCs of senescence-accelerated mice, similarly with previous data reported in human samples [24,25,34,72]. In our study, both α-syn/Aβ 1−42 and α-syn/tau concentrations in RBCs were signi cantly lower in AD patients than HC, as previously reported [35].…”