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The Levy Laboratory Describes a Method to Isolate a Novel Type of Extracellular Vesicle from the Brain

A new paper published in Nature Protocols by Pasquale D'Acunzo, Yohan Kim, Jonathan M. Ungania, Rocío Pérez-González, Chris N. Goulbourne, and Efrat Levy, all current or former members of the Center for Dementia Research (CDR), describes in great detail a method to isolate, fractionate, and analyze subpopulations of extracellular vesicles from the extracellular space of the brain. Extracellular vesicles are very small membrane-bound, heterogeneous, spherical structures containing proteins, RNA, and DNA that shuttle from cells into the extracellular milieu and from one cell to the other in order to eliminate waste from cells and to exchange information and material between cells.

Typical hallmarks of neurodegenerative diseases such as Alzheimer’s disease include the spreading of pathology from a single focal site to the rest of the brain and impairment in the processing of material, which eventually accumulates both inside and outside the cells, becoming toxic to neurons. Extracellular vesicles have roles in both the maintenance of homeostasis in the normal brain and in pathological processes in neurodegenerative disorders. Therefore, they have attracted scientific interest, growing exponentially in the last decade.

Pathogenic hotspots in the brain during aging, in neurodegenerative, neurodevelopmental, and psychiatric disorders include mitochondrial failure and endosomal-lysosomal system dysfunction, which likely play causative roles in neuron degeneration. Separation and identification of different subtypes of extracellular vesicles enable the discovery of roles that the different types of vesicles play in these conditions and initiate the development of novel therapeutic and diagnostic tools, capitalizing on the biology of brain extracellular vesicles.

The Levy laboratory is an international leader in the study of extracellular vesicles in the brain and was the first in 2012 to report a method to isolate these vesicles from the brain, paving the way for a new line of research in the field. Through the intervening decade, the laboratory has continuously worked to improve this method in order to identify the heterogeneity of extracellular vesicles in the brain. The culmination of these efforts led to the development of a high-resolution fractionation technique that separates eight extracellular vesicle subpopulations, including a previously unidentified subtype of extracellular vesicles of mitochondrial origin that the authors named mitovesicles. The final, improved method is described in the recently published paper in Nature Protocols in great detail.

 

Reference: D'Acunzo P, Kim Y, Ungania JM, Pérez-González R, Goulbourne CN, Levy E. Isolation of mitochondria-derived mitovesicles and subpopulations of microvesicles and exosomes from brain tissues. Nat Protoc. 2022 Aug 12. doi: 10.1038/s41596-022-00719-1. PMID: 35962195.

Dr. Ralph Nixon Receives Oskar Fischer Gold Prize

Ralph A. Nixon, Ph.D., M.D., Director of NKI’s Center for Dementia Research, has spent the last three decades working to uncover the fundamental cellular basis of Alzheimer’s disease. This work by Dr. Nixon and his laboratory has been recognized with the awarding of the Oskar Fischer Prize, an international competition to expand society’s understanding of the causes of Alzheimer’s. Dr. Nixon is one of four gold prize recipients.

James Truchard, whose philanthropic gift established the Oskar Fischer Prize, said that “The Prize’s goal is to bring forth ideas which can create a foundation for future research. While no single entry covered all the major aspects of Alzheimer’s, I believe a combination of these ideas creates a launchpad for future research.”

Dr. Nixon’s research centers around the disruption of the brain’s endosomal-lysosomal and autophagy network, the apparatus in the cell that serves to clear out degenerated proteins and helps rejuvenate the cell. The idea is that a fundamental issue in Alzheimer’s disease is the failure to recycle abnormal waste and proteins, which end up accumulating and can become toxic.

See The Oskar Fischer Prize website and the press release for more information about the Prize and the award recipients.

Nixon Lab Provides Further Evidence for Alternative Alzheimer’s Theory

A new open access paper in Nature Neuroscience by Ju-Hyun Lee, PhD, Center for Dementia Research (CDR) Director Ralph Nixon, MD, PhD, and colleagues presents the latest evidence from the Nixon Lab challenging the prevailing theory of how Alzheimer’s disease originates.  Rather, this research suggests that Alzheimer’s disease develops due to lysosomal dysfunction within cells, causing waste buildup which is a precursor to the extracellular amyloid plaques characteristic of Alzheimer’s. The paper by Lee et al. is featured on the June issue cover of Nature Neuroscience.

CDR Research Scientist Ju-Hyun Lee, who led the study, comments that “Our results for the first time sources neuronal damage observed in Alzheimer’s disease to problems inside brain cells’ lysosomes where amyloid beta first appears. Previously, the working hypothesis mostly attributed the damage observed in Alzheimer’s disease to what came after amyloid buildup outside of brain cells, not before and from within neurons.”

According to senior investigator Dr. Nixon, “This new evidence changes our fundamental understanding of how Alzheimer’s disease progresses; it also explains why so many experimental therapies designed to remove amyloid plaques have failed to stop disease progression because the brain cells are already crippled before the plaques fully form outside the cell. Our research suggests that future treatments should focus on reversing the lysosomal dysfunction and rebalancing acid levels inside the brain’s neurons.”

Alzforum, a networking site for Alzheimer’s research, highlights the article by Lee et al. in a piece titled “Behold PANTHOS, a Toxic Wreath of Perinuclear Aβ That Kills Neurons” which has received numerous comments.

CDR coauthors of this paper are Dun-Sheng Yang, Chris Goulbourne, Eunju Im, Philip Stavrides, Anna Pensalfini, Cynthia Bleiwas, Martin Berg, Chunfeng Huo, James Peddy, Monika Pawlik, Efrat Levy, and Mala Rao. To read more about these findings, see the NYU press release.

 

Reference: Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, Chan H, Bouchet-Marquis C, Bleiwas C, Berg MJ, Huo C, Peddy J, Pawlik M, Levy E, Rao M, Staufenbiel M, Nixon RA. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022 Jun 2. doi: 10.1038/s41593-022-01084-8.

Dr. Crystal Lewis Receives Faculty Mentorship Award

Crystal Lewis, PhD, Director of the Social Solutions & Services Division at NKI, received the NYU Department of Psychiatry’s “Research Mentorship of Faculty Award” in recognition of her exceptional mentorship and career development contributions. Dr. Lewis’s nominations for this award highlighted her work in social justice as informing her mentoring, and her impact through her committee work and professional organizations to mentor and support the scientific research careers of many including those with minoritized intersecting identities and those focused on research aimed at eliminating racial, ethnic, and other forms of health inequities. The award was announced at the NYU Psychiatry Department virtual Town Hall Meeting held on June 2.

New Depression Treatment Shows Promise

Dan Iosifescu, MD, Professor of Psychiatry at New York University School of Medicine and Director of Clinical Research at NKI, is the senior author of a new paper reporting promising results for an experimental treatment for major depressive dirsorder. The publication is a collaboration with Axsome Therapeutics and appears in The American Journal of Psychiatry. In this phase 2 clinical trial, the researchers compared a combined dextromethorphan-bupropion treatment (AXS-05) with the use of bupropion alone. They found that patients who received the combined treatment were significantly more likely to experience a reduction in symptoms of depression. In the press release from Axsome Therapeutics, Dr. Iosifescu commented: “Due to its novel mechanism of action targeting glutamate and sigma-1 receptors, and to its robust antidepressant efficacy demonstrated in this study, AXS-05 has the potential to become an important and very useful new treatment for patients with major depressive disorder.” For more details about the study, see this Psychiatric News Alert from the American Psychiatric Association.

 

Reference: Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. Am J Psychiatry. 2022 May 18:appiajp21080800. doi: 10.1176/appi.ajp.21080800. Epub ahead of print. PMID: 35582785.