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Targeting Amyloid beta production for Alzheimer’s Disease

Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes

Journal ClubJournal Club
 

Journal Club with Dr. Oliver Medvedik will return on November 23rd at 12:00 Eastern live on our Facebook page. A new study appears to have solved the mystery of how amyloid beta, a key player in Alzheimer’s, forms in brain nerve cells. The data suggests that the sigma-1 receptor may be a therapeutic target for reducing Amyloid beta production, specifically in axons.

Abstract

Axonal generation of Alzheimer’s disease (AD)-associated amyloid-β (Aβ) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a preferred substrate for β-secretase. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are cholesterol-rich lipid rafts that are upregulated in AD. Here, we show that downregulating MAM assembly by either RNA silencing or pharmacological modulation of the MAM-resident sigma1 receptor (S1R) leads to attenuated β-secretase cleavage of palAPP. Upregulation of MAMs promotes trafficking of palAPP to the cell surface, β-secretase cleavage, and Aβ generation. We develop a microfluidic device and use it to show that MAM levels alter Aβ generation specifically in neuronal processes and axons, but not in cell bodies. These data suggest therapeutic strategies for reducing axonal release of Aβ and attenuating β-amyloid pathology in AD.

Literature

Bhattacharyya, R., Black, S. E., Lotlikar, M. S., Fenn, R. H., Jorfi, M., Kovacs, D. M., & Tanzi, R. E. (2021). Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes. Cell Reports35(7), 109134.

CategoryJournal club, News
About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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