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

Abstract

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.

Fluid‐based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases

“…However, recent studies have reported increased P‐tau concentrations in neuron‐derived exosomes isolated from serum using antibodies directed against neuron‐enriched proteins (Shi et al . ; Winston et al . ).…”

Mass spectrometry: A platform for biomarker discovery and validation for Alzheimer's and Parkinson's diseases

“…; Shi et al . ). One recent development, reported by two independent studies, is the significantly different Aβ 42 /Aβ 40 ratio among amyloid positive versus negative patients which may provide improved diagnosis for patients with ambiguous CSF Aβ 42 or tau results, and may have sparked some hope back into blood‐derived biomarked development for AD (Ovod et al .…”

“…Furthermore, we have recently used immunoassay detection platforms to report that CNS‐derived EVs within plasma of the contain altered levels of α‐syn and tau in PD (Shi et al . ; Shi et al ., ). These studies hint at the potential utility of plasma EVs as a future biomarker resource that maintains the clinical ease of blood collection but avoids many of the complications involved with blood alone.…”

“…)], and recent work suggests that this can also include key proteins involved with AD and PD such as tau (Shi et al . ), Aβ 42 (Takahashi et al . ), and α‐syn (Coleman & Hill ; Budnik et al .…”

Sphingolipid-Enriched Extracellular Vesicles and Alzheimer’s Disease: A Decade of Research

“…As such, the results may not necessarily reflect contents of a bona fide exosome population but include other lipid vesicles as well. In contrast, an independent group recently reported that tau was not found to be associated at higher levels with neural-derived EVs isolated from plasma of AD patients [90]. Using isolation of neural-derived EVs from human plasma, it was also found that the abundance of several proteins was altered up to 10 years prior to AD diagnosis [91].…”