Alpha-synuclein levels in blood plasma decline with healthy aging.

There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years) compared to younger (avg. 27.6 years) individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001), possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.

Altered serum IgG levels to α-synuclein in dementia with Lewy bodies and Alzheimer's disease.

Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against α-synuclein is not well known. We explored serum IgG levels to monomeric α-synuclein in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-α-synuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against α-synuclein in DLB and AD, which may relate to a disturbed α-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target α-synuclein in neurodegenerative disease.