Professor, Department of Psychiatry
Professor, Department of Biochemistry and Molecular Pharmacology
A major focus of research in the laboratory has been to identify the factors that initiate and propagate pathology in neurodegenerative disorders. Using multidisciplinary approaches, we have been studying cell biological processes that can be modified to protect neurons and the brain during aging and from neurodegenerative diseases.
In recent years we have been studying vesicular trafficking, foundational studies that have allowed us to develop the models and methods to examine the role of extracellular vesicles as either protective or pathogenic vehicles within the brain. The elimination of cytotoxic material from the cell via extracellular vesicles, including exosomes and microvesicles, can spread toxic material in the central nervous system, promoting the development of neurodegenerative diseases such as Alzheimer’s disease (AD). AD is a chronic neurodegenerative disorder, one of the leading causes of death among the elderly. A central pathological feature of the disease is the accumulation of amyloid b in the brain and extensive evidence suggests that amyloid b has an important role in the disease process, leading to the brain dysfunction characterizing patients. We found that human and mouse brain extracellular vesicles are enriched with the carboxyl-terminal fragments of the amyloid b precursor protein (APP), neurotoxic proteins that are a source of amyloid b, suggesting a pathogenic role in propagation of amyloid b-pathology throughout the brain. Paradoxically, our findings also suggest that the secretion of extracellular vesicles is a mechanism for the clearance of endocytic vesicular content when disease-mediated dysfunctions in the endosomal-lysosomal pathway prevent the efficient transport of cargo for degradation in the lysosomes. Ongoing studies are investigating the effects of endosomal-lysosomal and autophagic abnormalities on extracellular vesicles secretion and both the protective and pathogenic function/s of brain extracellular vesicles.
We are also investigation a neuroprotective role of extracellular vesicles as carriers of protective proteins in the brain extracellular space and through their uptake by brain cells. In one project, we are investigating extracellular vesicles as carriers of an anti-amyloidogenic protein. In an Italian ancestral line with a familial form of AD, a mutated form of amyloid b inhibits the accumulation and neurotoxicity of amyloid b, preventing the development of the disease. The research is investigating the mechanism(s) by which the Italian form of amyloid b exerts its protection. In parallel, we have been studying the neuroprotection activities of cystatin C. We demonstrated that cystatin C alleviates endosomal-lysosomal abnormalities and memory deficits in mouse models of Down syndrome and of progressive myoclonus epilepsy, and our current studies have shown that cystatin C enhances secretion of extracellular vesicles – suggesting a mechanism by which cystatin C can be neuroprotective in neurodegenerative disorders with endosomal and/or extracellular vesicles disruption. Furthermore, these studies utilize extracellular vesicles as protective vehicles. Extracellular vesicles transport their content for long distances through the extracellular space and into recipient cells and would deliver the protective proteins, providing a novel therapeutic approach for AD.
Cell reports. 2020 Oct 06; 33(1):108236
Neurobiology of aging. 2019 Aug 01; 84:26-32
Scientific reports. 2019 Jul 31; 9(1):11104
Developmental neurobiology. 2019 Jul; 79(7):656-663
Brain. 2019 Jan 01; 142(1):163-175
Frontiers in neuroscience. 2019 Jan; 13:1347
Neurobiology of disease. 2018 Dec; 120:165-173