alpha-Synuclein in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment

Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health (NIH)) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514, P42 ES004696-5897, P30 ES007033-6364]; NIA [R01 AG033398]; NIEHS [R01 ES016873, R01 ES019277]; NINDS [R01 NS057567, P50 NS062684-6221, U01 NS082137]In addition to amyloid-beta (A beta) and tau, alpha-synuclein, best known for its role in Parkinson's disease (PD), has been suggested to be involved in cognition and pathogenesis of Alzheimer's disease (AD). We investigate the potential of alpha-synuclein in cerebrospinal fluid (CSF) as a biomarker of cognitive decline in AD, and its prodromal phase, mild cognitive impairment (MCI). Using an established, sensitive Luminex assay, we measured alpha-synuclein levels in the CSF of a cohort of close to 400 healthy control, MCI, and AD subjects obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and factored in APOE genotype in data analysis. CSF alpha-synuclein levels were significantly higher in the MCI (p = 0.005) and AD (p < 0.001) groups, compared to controls. However, receiver operating characteristic (ROC) curve analysis suggests that CSF alpha-synuclein level on its own only offered modest sensitivity (65%) and specificity (74%) as a diagnostic marker of AD, with an area under the curve (AUC) value of 0.719 for AD versus controls. The effect of APOE genotype, if any, was quite subtle. However, there was a significant correlation between alpha-synuclein and cognition (p = 0.001), with increased alpha-synuclein levels associated with decreased Mini-Mental State Exam scores. Our results support a role for alpha-synuclein even in MCI, the early phase of AD, in addition to being a potential contributor in MCI and AD diagnosis or monitoring of disease progression

Cheek cell–derived α-synuclein and DJ-1 do not differentiate Parkinson's disease from control

Recently, α-synuclein (α-syn) and DJ-1, 2 proteins critically involved in Parkinson's disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or sex) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as 1 of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, albeit largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD

Cheek cell–derived α-synuclein and DJ-1 do not differentiate Parkinson's disease from control

Recently, α-synuclein (α-syn) and DJ-1, two proteins critically involved in Parkinson’s disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or gender) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as one of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, though largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD

CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease

IntroductionAlzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood.MethodsTau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects.ResultsThe efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau.ConclusionsTau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD

CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease

BACKGROUND: Alzheimer disease (AD) and Parkinson disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. METHODS: Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by Single Molecule Array technology with 303 subjects. RESULTS: The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls, and correlated with cerebrospinal fluid tau. CONCLUSIONS: Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD