Research

Roles of brain mitovesicles in neurodegeneration

D’Acunzo Lab primarily study how changes in small extracellular vesicles of mitochondrial origin (mitovesicles) detected in the brain extracellular space of patients with Alzheimer’s disease (AD) and people with Down syndrome (DS) impact the regulation of brain homeostasis and the activity of neurons. The laboratory demonstrated that several AD-risk factors, including aging, apolipoprotein E genotype, and high levels of the amyloid β precursor protein are linked to concomitant profound alterations to both mitochondria and mitovesicle biogenesis, content, and secretion. While studying the functional consequences of these changes, it was discovered that mitovesicles isolated from the brain of a mouse model of DS, impair long-term potentiation (a molecular mechanism important for memory formation) in wild-type hippocampi. Other extracellular vesicle fractions enriched with either ectosomes or exosomes isolated from the same DS brains and all types of extracellular vesicles isolated from the brain of disomic controls did not affect long-term potentiation. Studies have shown that monoaminoxidase B, a protein that is pivotal for the homeostasis of neurotransmitters, causes this electrophysiological effect. This novel and largely unexplored field of research has the potential to determine how mitochondrial abnormalities (a hallmark of AD and DS) spread in the brain during neurodegeneration and to define whether and how mitovesicles contribute to memory deficits in AD, with the ultimate goal of developing unexplored, mitovesicle-centered targets for therapeutic intervention.