Raja Bhattacharyya, Ph.D.

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

Dr. Raja Bhattacharyya (he/him) is a cell biologist who studies the cellular and molecular mechanisms of Alzheimer’s disease (AD) pathology. Dr. Bhattacharyya received his Ph.D. from Jadavpur University, Bose Institute, Calcutta, India. In his doctoral thesis, he studied fatty acylation of erythrocyte membrane protein 4.2 in chronic myeloid leukemia. In his post-doctoral research, Dr. Bhattacharyya uncovered aspects of fatty acylation, specifically palmitoylation, in regulating subcellular localization and functions of oncogenic proteins, namely, Galpha12/13 and Rho/Rac GTPases. Later, Dr. Bhattacharyya extended his understanding of protein fatty acylation in AD research to first demonstrate that the beta-amyloid precursor protein APP is palmitoylated. He showed that palmitoylated APP (palAPP) and/or its dimerized form in lipid rafts are potential therapeutic targets for AD.

Dr. Bhattacharyya is an Assistant Professor of Neurology at Massachusetts General Hospital, Harvard Medical School. Dr. Bhattacharyya’s current research revealed that palAPP is stabilized and is prepared for cleavage by beta-secretase in special lipid rafts within the neuron known as mitochondria-associated ER membranes (MAMs). Most notably, Dr. Bhattacharyya’s research shows not only that the MAM is where palAPP is processed by beta-secretase to make Abeta but that this happens exclusively in axons and neuronal processes where Abeta does most of its damage. His findings have significantly advanced the understanding of the cellular and molecular mechanisms underlying APP processing/trafficking and Abeta generation in axons and synapses. Dr. Bhattacharyya’s current research focuses on studying the effect of de-palmitoylating agents and cholesterol-modifying agents on Abeta generation from MAM-associated palAPP, specifically from axons and neuronal processes. This research carries major implications for developing novel AD therapies based on targeting MAM-associated palAPP in neuronal processes and axons to ameliorate neuritic and synaptic Abeta pathology.

Dr. Bhattacharyya has diverse research interests. He has recently identified a crosstalk between two AD-risk genes, BIN1 and RIN, in regulating endocytosis and endosomal homeostasis in AD development. In an in vitro study, Dr. Bhattacharyya reported that the neuronal isoform of BIN1 specifically regulates APP endocytosis in a RIN3-dependent manner. He is now studying the role of BIN1 and RIN3 interaction in the development of AD using 3D neural, hiPSC, and animal models of AD. He is also developing a peptide-based therapeutic strategy to lower Abeta production by segregating APP from BACE1 in endosomes, or by reducing endosomal dyshomeostasis, specifically endosomal enlargement by regulating RIN3-mediated endosomal recruitment of BIN1 in early-endosomes. Endosomal abnormalities, such as the accumulation of enlarged endosomes, are found in AD neurons long before amyloid or Tau pathology appears. Dr. Bhattacharyya’s research has enormous potential in developing therapies that target both the early and late stages of AD. Given the complexity of AD, therapeutic strategies that address multiple aspects of its pathology are likely to be more effective in developing effective therapeutics targeting the early- or late-stage pathology of AD.



Funded Research

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

Selected Publications

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

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., 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., 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

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