Levy Lab

Head of Lab

Changes in Vesicular Trafficking in Alzheimer’s Disease Neurons

Research in the Levy Lab, led by Efrat Levy, PhD, aims to understand the pathogenic processes that lead to Alzheimer’s disease (AD) and related neurodegenerative disease. In recent years, our focus has been on changes in vesicular trafficking in neurons during the disease, including what are now foundational studies of the role of extracellular vesicles as either protective or pathogenic vehicles within the brain. Our findings suggest that the secretion of extracellular vesicles is a mechanism for the clearance of accumulated material when disease-mediated dysfunctions prevent the efficient transport of cargo for degradation inside the cell. Ongoing studies are investigating the effects of neuronal abnormalities on extracellular vesicles secretion and the utilization of extracellular vesicles as protective vehicles. Extracellular vesicles transport their content for long distances through the extracellular space and into recipient cells and can deliver protective proteins, such as cystatin C, and other molecules, providing a novel therapeutic approach for AD. In one project, we are investigating the enhanced release of extracellular vesicles as a potential therapy, preventing neuronal loss in the brain due to accumulation of toxic material. We are also studying the apolipoprotein E (APOE) genotype, an important determinant of an individual’s risk for developing AD. While the APOE2 allele appears to be protective, APOE4 increases the risk for the disease as compared with carriers of the neutral-risk APOE3 allele. Additionally, APOE4 expression can lead to cognitive decline during aging that is independent of characteristic AD pathology. Our data show neuronal abnormality in the brain of APOE4 carriers and lower levels of extracellular vesicles released into the brain extracellular space. Compromised vesicle production is likely to have adverse effects, diminishing a cell’s ability to eliminate accumulated toxic material, leading to neuron vulnerability in APOE4-expressing individuals. Extracellular vesicular dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of APOE4 expression, contributing to higher risk of developing AD. Moreover, we found that in brain, APOE2 drives higher exosome number with age when compared with APOE3 mice.

We are currently investigating the changes in the brain of carriers of APOE4 allele as compared with the APOE2 allele to identify therapeutic targets based on the differences in release and content of extracellular vesicles due to the different APOE genotypes. In order to investigate the interrelationship between pathology in the endosomal-lysosomal pathway and release of extracellular vesicles, we developed a method for the isolation of extracellular vesicles from brain tissue, a method we initially published in 2012, with additional details in 2017. We further modified this method, contributing to the identification of a novel type of mitochondria-derived extracellular vesicles that we termed mitovesicles.

Mitochondrial dysfunction is an established hallmark of aging and neurodegenerative disorders. We found that the levels and cargo of mitovesicles increase during pathophysiological processes where mitochondrial dysfunction occurs, including in the brain of Down syndrome individuals and during aging. We are currently investigating the protective role of all types of extracellular vesicles in the brain, as well as their contribution to the propagation of disease throughout the brain. Our translational research also involves the delivery of proteins and peptides that prevent the development of AD via extracellular vesicles.

Selected Publications

D'Acunzo P, Pérez-González R, Kim Y, Hargash T, Miller C, Alldred MJ, Erdjument-Bromage H, Penikalapati SC, Pawlik M, Saito M, Saito M, Ginsberg SD, Neubert TA, Goulbourne CN, Levy E. Mitovesicles are a novel population of extracellular vesicles of mitochondrial origin altered in Down syndrome. Sci Adv. 2021 Feb 12;7(7):eabe5085. doi: 10.1126/sciadv.abe5085. PMID: 33579698; PMCID: PMC7880603
Click for abstract

Pérez-González R, Sahoo S, Gauthier GA, Kim Y, Li M, Kumar A, Pawlik M, Benussi L, Ghidoni R, Levy E. Neuroprotection mediated by cystatin C-loaded extracellular vesicles. Scientific Reports. 2019;9(1):11104. DOI: 10.1038/s41598-019-47524-7. PMID: 31367000; PMCID: PMC6668451

Click for abstract

Gauthier GA, Pérez-González R, Sharma A, Huang F-K, Alldred MJ, Pawlik M, Kaur G, Ginsberg SD, Neubert TA, Levy E. Enhanced exosome secretion in Down syndrome brain – a protective mechanism to alleviate neuronal endosomal abnormalities. Acta Neuropathol Commun. 2017;5(1):65. DOI: 10.1186/s40478-017-0466-0. PMID: 28851452; PMCID: PMC5576289

Click for abstract

Publications

All publications

Levy Lab Members

Adaora Aroh Research Support Assistant 845-398-6669 Adaora.Aroh@NKI.rfmh.org	Kyle Casey Research Support Assistant 845-398-6669 Kyle.Casey@nki.rfmh.org	Pasquale D'Acunzo, PhD Postdoctoral Researcher 845-398-6669 Pasquale.DAcunzo@nki.rfmh.org	Steven DeRosa Research Support Assistant 845-398-6669 Steven.Derosa@NKI.rfmh.org
Yohan Kim, PhD Postdoctoral Researcher 845-398-5532 Yohan.Kim@NKI.rfmh.org	Monika Pawlik, PhD Postdoctoral Researcher 845-398-6664 Monika.Pawlik@NKI.rfmh.org	Kathy Peng, PhD Postdoctoral Researcher 845-398-7751 Kathy.Peng@NKI.rfmh.org	Lital Rachmany Raber, PhD Postdoctoral Researcher 845-398-6669 Lital.RachmanyRaber@NKI.rfmh.org
Kyle Smith Research Support Assistant 845-398-6669 Kyle.Smith@NKI.rfmh.org	Jonathan Ungania Research Support Assistant 845-398-6669 Jonathan.Ungania@NKI.rfmh.org	Giorgio Zaghen Research Support Assistant 845-398-6669 Giorgio.Zaghen@NKI.rfmh.org