biochemical-purification-proteomic-characterization-amyloid-fibril

Biochemical Purification and Proteomic Characterization of Amyloid Fibril Cores from the Brain

Proteinaceous fibrillar inclusions are key pathological hallmarks of multiple neurodegenerative diseases. In the early stages of Alzheimer&#39;s disease ...

Northwestern University Feinberg School of Medicine

Extracellular vesicles (EVs) are important mediators of intercellular communication. Interest in the role of central nervous system (CNS)-derived EVs has been increasing; however, some skepticism of their importance has persisted because many aspects of their biology remain elusive. This ambiguity is largely due to technical barriers that hamper our ability to achieve a comprehensive understanding of their molecular components and mechanisms responsible for their transmission and uptake. However, accumulating evidence supports the notion that EVs play important roles in basic physiological processes within the CNS during neurodevelopment and synaptic plasticity. Interestingly, EVs also act to spread toxic polypeptides in neurodegenerative diseases. Developing a more profound understanding of the role that EVs play in the CNS could lead to the identification of biomarkers and potential vehicles for drug delivery. Here we highlight our current understanding of CNS EVs and summarize our current understanding of their complex role in the CNS.

The Dichotomous Role of Extracellular Vesicles in the Central Nervous System.

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aβ accumulation, the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV)-associated proteins, have elevated levels, misfold in both a plaque-dependent and -independent manner, and interact with APP and Aβ. Concurrent with elevated levels of SV-associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology. A record of this paper's transparent peer review process is included in the Supplemental Information.

Article	Year
The Dichotomous Role of Extracellular Vesicles in the Central Nervous System. iScience\| PubMed ID: 32835924	2020
Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals. Cell systems\| PubMed ID: 33326751	2021

Arun Upadhyay

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