Brain Endothelium-derived Extracellular Vesicles Containing Amyloid-beta Induce Mitochondrial Alterations in Neural Progenitor Cells

Overview

Journal Extracell Vesicles Circ Nucl Acids

Date 2023 Jan 17

PMID 36649440

Authors

Olivia M Osborne

Jennifer M Kowalczyk

Kelssey D Pierre Louis

Manav T Daftari

Brett M Colbert

Oandy Naranjo

Silvia Torices

Ibolya E Andras

Derek M Dykxhoorn

Michal Toborek

Affiliations

Soon will be listed here.

Abstract

Aim: Elevated brain deposits of amyloid beta (Aβ) contribute to neuropathology and cognitive dysfunction in Alzheimer's disease (AD). However, the role of the blood-brain barrier (BBB) as an interface for the transfer of Aβ from the periphery into the brain is not well characterized. In addition, a substantial population of neural progenitor cells (NPCs) resides in close proximity to brain capillaries that form the BBB. The aim of this study is to understand the impact of brain endothelium-derived extracellular vesicles (EV) containing Aβ on metabolic functions and differentiation of NPCs.

Methods: Endothelial EVs were derived from an model of the brain endothelium treated with 100 nM Aβ or PBS. We then analyzed the impact of these EVs on mitochondrial morphology and bioenergetic disruption of NPCs. In addition, NPCs were differentiated and neurite development upon exposure to EVs was assessed using the IncuCyte Zoom live cell imaging system.

Results: We demonstrate that physiological concentrations of Aβ can be transferred to accumulate in NPCs via endothelial EVs. This transfer results in mitochondrial dysfunction, disrupting crista morphology, metabolic rates, fusion and fission dynamics of NPCs, as well as their neurite development.

Conclusion: Intercellular transfer of Aβ is carried out by brain endothelium-derived EVs, which can affect NPC differentiation and induce mitochondrial dysfunction, leading to aberrant neurogenesis. This has pathological implications because NPCs growing into neurons are incorporated into cerebral structures involved in learning and memory, two common phenotypes affected in AD and related dementias.

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