Extracellular Vesicles

Alzheimer’s Disease (AD) is a devastating neurological disorder that remains the underlying cause of dementia for millions of people around the world. Despite many questions surrounding the mechanisms of AD development and progression, pronounced senile plaques, composed of the neurotoxic β-amyloid (Aβ) peptide, in the extracellular space of the brain remain one of the hallmark presentations of AD. Recent evidence demonstrates that APP (amyloid precursor protein), a single pass transmembrane protein that gives rise to Aβ, and Aβ are packaged into a smaller subset of extracellular vesicles (EVs) called exosomes. These endosomal derived vesicles are capable of transmitting APP and pathogenic Aβ fragments to nearby target cells, inducing neurotoxicity and subsequent inflammatory responses in these cells and potentially contributing to the propagation of AD pathology. Considering the emerging biological significance of exosomes in the context of AD, as well as in a great swath of other physiological functions and pathologies, EV-based therapies utilizing exogenous mesenchymal stem cell-derived EVs (MSC EVs) are being thoroughly investigated as an AD intervention strategy. These studies report promising therapeutic effects of MSC EVs in mouse models of AD, attributing them to reduced neuroinflammation, increased neurogenesis, and enhanced Aβ clearance. Recent findings from our laboratory demonstrate the capacity of 3-D MSC aggregates to produce a greater number of small EVs enriched with anti-inflammatory miRNA, potentially implicating them as a more effective therapeutic agent to treat Alzheimer’s disease. To emphasize the diverse biological significance of extracellular vesicles, the focus of this project was to demonstrate extracellular vesicles as both a pathogenic mediator and therapeutic agent in AD by: 1) Determining the effect of mutant APP processing on EV production and cargo 2) Determining the efficacy of 3-D cultured MSC EVs to hinder Alzheimer’s disease progression in a 5xFAD mouse model.