Cure Alzheimer's Fund Cure Alzheimer's Fund

Raja Bhattacharyya, Ph.D.

Assistant Professor of Neurology, Harvard Medical School; Faculty, Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital

I am an Assistant Professor of Neurology at Massachusetts General Hospital and Harvard Medical School. My research focus is to understand the cellular and molecular mechanisms of Alzheimer’s disease (AD) pathophysiology. A key feature of Alzheimer’s disease (AD) is the formation of amyloid plaques in the brain decades before symptoms of dementia occur. Recently, I have extensively employed a 3D neural cell model of AD incorporating human embryonic stem cell-derived neural cells expressing familial AD mutations to demonstrate that the raft-like membranes found juxtaposed between mitochondria and endoplasmic reticulum (MAMs) play a significant role in trafficking and beta-secretase-mediated processing of a critical pool of palmitic acid-modified amyloid precursor protein (palAPP) to make amyloid beta, but that this happens exclusively in axons and neuronal processes where amyloid beta does most of its damage. My work has opened a new avenue to understand one of the major mysteries in AD: how toxic amyloid beta is made in the axons of the brain’s nerve cells.

Genomic studies have identified BIN1 (Bridging integrator 1) and RIN3 (Ras and Rab interactor 3) as genetic risk factors for late-onset Alzheimer’s disease (LOAD). BIN1 (product of the BIN1 gene) and RIN3 (product of the RIN3 gene) directly interact to regulate RAB5-mediated endocytosis in neurons, which is an essential step for beta-secretase-mediated processing of APP and amyloid beta production in endosomes. My recent studies have shown that the neuronal isoform, but not the non-neuronal isoform of BIN1, regulates amyloid beta generation by altering APP endocytosis in a RIN3-dependent manner. My current goal is to employ 3D neural models of AD, human-derived induced pluripotent stem cells (hiPSCs), and conditional knock-out animal models to understand the role of BIN1 and RIN3 interaction in the neuron for the development of early- and/or late-stage AD pathology. These findings will open new avenues to develop novel AD therapies by targeting the molecular pathways that regulate BIN1 and RIN3 interaction in neurons to modulate endosomal homeostasis and amyloid beta production in AD.

 

Related Research:

Role of Stabilization of MAMs and MAM-Associated Palmitoylated APP (MAM-palAPP) in Alzheimer’s Disease Raja Bhattacharyya 2023-11-02 Role of Ras and Rab Interactor 3 (RIN3) and Bridging Integrator 1(BIN1) Interaction in the Neurons for Alzheimer’s Disease Development Raja Bhattacharyya 2023-07-10 Effects of Depalmitoylation and ACAT Inhibition on Axonal Amyloid Beta Generation Via MAM-Associated palAPP Raja Bhattacharyya Rudy Tanzi 2022-02-10

Funded Research

These projects were made possible from Cure Alzheimer's Fund support.

Project Description Researchers Funding
Role of Stabilization of MAMs and MAM-Associated Palmitoylated APP (MAM-palAPP) in Alzheimer’s Disease 2023, 2024

$402,500
Role of Ras and Rab Interactor 3 (RIN3) and Bridging Integrator 1(BIN1) Interaction in the Neurons for Alzheimer’s Disease Development 2023, 2024

$420,500
Effects of Depalmitoylation and ACAT Inhibition on Axonal Amyloid Beta Generation Via MAM-Associated palAPP 2021, 2022

$345,000

Selected Publications

These published papers resulted from Cure Alzheimer’s Fund support.

Wlodarczyk, J., Bhattacharyya, R., Dore, K., Ho, G. P. H., Martin, D. D. O., Mejias, R., & Hochrainer, K. Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders, The Journal of Neuroscience, October 2, 2024, Read More

Bhattacharyya, R., & Kovacs, D. M. ACAT Inhibition and amyloid beta reduction, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, August 1, 2010, Read More

Bhattacharyya, R., Barren, C., & Kovacs, D. M. Palmitoylation of Amyloid Precursor Protein regulates amyloidogenic processing in lipid rafts, Journal of Neuroscience, July 3, 2013, Read More

Huttunen, H. J., Peach, C., Bhattacharyya, R., Barren, C., Pettingell, W., Hutter-Paier, B., Windisch, M., Berezovska, O., & Kovacs, D. M. Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway, The FASEB Journal, July 22, 2009, Read More

Bhattacharyya, R., Teves, C. A. F., Long, A., Hofert, M., & Tanzi, R. E. The neuronal-specific isoform of BIN1 regulates β-secretase cleavage of APP and Aβ generation in a RIN3-dependent manner, Scientific Reports, March 3, 2022, Read More

Lotlikar, M. S., Tarantino, M. B., Jorfi, M., Kovacs, D. M., Tanzi, R. E., & Bhattacharyya, R. Microfluidic separation of axonal and somal compartments of neural progenitor cells differentiated in a 3D matrix, STAR Protocols, January 7, 2022, Read More

Bhattacharyya, R., Black, S. E., Lotlikar, M. S., Fenn, R. H., Jorfi, M., Kovacs, D. M., & Tanzi, R. E. Axonal generation of amyloid-β from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes, Cell Reports, May 18, 2021, Read More

Bhattacharyya, R., Fenn, R. H., Barren, C., Tanzi, R. E., & Kovacs, D. M. Palmitoylated APP forms Dimers, Cleaved BACE1, PLoS One, November 22, 2016, Read More

Back to Our Researchers