Pasquale D'Acunzo, PhD

Mitochondrial homeostasis is a point of heightened frailty during physiological aging and in neurodegenerative and neurodevelopmental disorders, including in patients with Alzheimer’s disease (AD) and in people with Down syndrome (DS). Mitochondrial dysfunction is one of the earliest pathological brain alterations found in AD and DS, decades before the onset of the clinical symptoms. Chronic damage to brain mitochondria induces metabolic alterations, spread of reactive oxygen species, synaptic deficits, and neuronal cell loss, making mitochondria an attractive target for therapeutic intervention.

Extracellular vesicles (EVs) are membrane-bound vesicles constitutively released into the extracellular space by all cell types. Our laboratory recently identified and characterized a novel subtype of small brain EVs derived from mitochondria that we named mitovesicles. Given the novelty of our discovery, the role of mitovesicles in the regulation of mitochondrial homeostasis and how altered mitochondria change mitovesicles during aging and in AD and DS is an unexplored field of research, and the main focus of our laboratory. We 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. We are currently studying the functional consequences of these changes. For example, we recently found that mitovesicles isolated from the brain of a mouse model of DS are overloaded with a protein that is pivotal for the homeostasis of neurotransmitters, monoaminoxidase B. Through this protein, DS (but not control) mitovesicles impair long-term potentiation, a molecular mechanism important for memory formation.

Our ultimate goal is to understand the bidirectional interrelationships between brain mitochondrial abnormalities and mitovesicle alterations in AD and DS, in order to define whether and how mitovesicles contribute to pathology propagation, as well as to develop unexplored, mitovesicle-centered targets for therapeutic intervention.