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Elevated levels of extracellular vesicles in progranulin-deficient mice and FTD-GRN Patients. | LitMetric

Elevated levels of extracellular vesicles in progranulin-deficient mice and FTD-GRN Patients.

Ann Clin Transl Neurol

Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Published: December 2020

AI Article Synopsis

  • The study investigates the impact of progranulin deficiency on extracellular vesicles (EVs) and their potential role in neurodegenerative diseases like frontotemporal dementia (FTD).
  • Researchers analyzed EV levels in both Grn mice, which model FTD-GRN-related lysosomal dysfunction, and in FTD-GRN patients, noting that altered EV levels correlate with disease symptoms.
  • Results showed that symptomatic FTD-GRN patients and Grn mice exhibit increased brain and plasma EV levels, suggesting these EVs could serve as biomarkers for monitoring FTD progression.

Article Abstract

Objective: The goal of this study was to investigate the effect of progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population of vesicles that may contribute to progression of neurodegenerative disease. Loss-of-function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD), and brains from GRN carriers with FTD (FTD-GRN) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain.

Methods: We analyzed levels and protein contents of brain EVs from Grn mice, which model the lysosomal abnormalities of FTD-GRN patients. We then measured brain EVs in FTD-GRN patients. To assess the relationship of EVs with symptomatic disease, we measured plasma EVs in presymptomatic and symptomatic GRN mutation carriers.

Results: Grn mice had elevated brain EV levels and altered EV protein contents relative to wild-type mice. These changes were age-dependent, occurring only after the emergence of pathology in Grn mice. FTD-GRN patients (n = 13) had elevated brain EV levels relative to controls (n = 5). Symptomatic (n = 12), but not presymptomatic (n = 7), GRN carriers had elevated plasma EV levels relative to controls (n = 8).

Interpretation: These data show that symptomatic FTD-GRN patients have elevated levels of brain and plasma EVs, and that this effect is modeled in the brain of Grn mice after the onset of pathology. This increase in EVs could influence FTD disease progression, and provides further support for EVs as potential FTD biomarkers.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732244PMC
http://dx.doi.org/10.1002/acn3.51242DOI Listing

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