Brain endothelium-derived extracellular vesicles containing amyloid-beta induce mitochondrial alterations in neural progenitor cells

Abstract

Aim: Elevated brain deposits of amyloid beta (Aβ₄₀) 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 Aβ₄₀ 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 Aβ₄₀ on metabolic functions and differentiation of NPCs.

Methods: Endothelial EVs were derived from an in vitro model of the brain endothelium treated with 100 nM Aβ₄₀ 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 Aβ₄₀ 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 Aβ₄₀ 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.

Keywords

Blood-brain barrier / mitochondrial bioenergetics / extracellular vesicle / neurogenesis / Alzheimer’s disease / Seahorse / neural progenitor cell

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