Bhattacharyya Lab

Research Overview

First Research Area: S1R-MAM Axis in AD

Alzheimer's disease (AD) is characterized by the accumulation of beta-amyloid (Abeta) peptides in the form of senile plaques, neurofibrillary tangles (NFTs), and neuroinflammation. Ab is considered the initial driver of AD neuropathogenesis. Immunotherapies by administering anti-Abeta monoclonal antibodies, such as Leqembi, lead to microglial clearance of amyloid deposits and slowed cognitive decline in patients with prodromal to mild AD. However, the high cost and safety concerns associated with anti-Abeta immunotherapy emphasize the urgent need for small-molecule alternatives targeting a broader range of therapeutic targets beyond the pathologic proteins. Among the alternatives, modulators of the sigma-1 receptors (S1R) exhibit notable anti-amnestic effects in pre-clinical studies of mild-to-moderate AD. S1R are highly expressed in the brains and is localized in the endoplasmic reticulum (ER) or at the contact areas between the ER and mitochondria, known as mitochondria‐associated ER membranes or MAMs. The recently coined “MAM hypothesis” suggests that MAMs initiate the pathogenic cascade of AD. MAMs are diverse in their structure and function. Structurally, MAM thickness or gap width that typically varies between the tightest (6 nm) to the widest (80 nm) regulate cellular functions involved in cell survival. Employing various human cellular models, including a three-dimensional (3D) human neural culture model of AD, we have identified a novel molecular axis where S1R-mediated modulation of MAM stabilization regulated axonal versus somal/neuronal Abeta levels, likely by modulating MAM gap width.

The role of neuronal Abeta in AD pathogenesis is well established. It is also known that Abeta, made in the brain’s axons and nerve endings, causes the worst damage in Alzheimer’s by impairing communication between neurons. Despite years of research, the role of axonal Abeta is less understood. Our current research is aimed at addressing the hypothesis that the sigma-1 receptors (S1R) regulate neuronal or axonal Ab levels by loosening or tightening the MAM gap widths in AD. Our goal is to provide mechanistic data to facilitate the development of efficacious AD therapeutics with minimum off-target effect by targeting the S1R-MAM axis. We use 3D neural model of AD, 3D dual chamber microfluidic devices, desomatized axons from mature neurons, and mouse optic nerve (physiological model of pure axons) for our studies. See Working Model (Fig. 1).

Second Research Area: BIN1-RIN3 Axis in AD

Genome-wide association studies have identified numerous endocytic trafficking genes significantly associated with AD risk. The endocytic trafficking gene BIN1 (bridging integrator 1) is one of the major susceptibility genes, second to APOE, for sporadic AD. Whole-exome sequencing (WES) analyses have recently identified RIN3 (Ras and Rab interactor 3) as an AD-risk gene. BIN1 (product of the BIN1 gene) and RIN3 (product of the RIN3 gene) interact to regulate RAB5-mediated endocytosis. Despite being a major AD risk gene, the role of BIN1 in AD is largely unknown primarily because there are at least 10 BIN1 splice variants with different tissue distributions and functions. Moreover, homozygous BIN1 knock-out mice are perinatally lethal. Our recently published in vitro study demonstrating that only the neuronal isoform of BIN1 (BIN1V1), but not the nonneuronal isoform BIN1V9, was recruited to the RAB5+ endosomes in a RIN3-dependent manner resulting in delayed endocytosis of APP and reduced Ab production. Abnormal endocytosis or endosomal homeostasis like endosomal enlargement are detected long before amyloid or tau pathology is observed. Our lab is currently studying the crosstalk between BIN1 and RIN3 in regulating endocytosis and/or endosomal homeostasis to provide a blueprint for developing novel therapies that can be administered pre-symptomatically to prevent or delay AD pathogenesis. We use 3D neural models, isogenic human induced pluripotent stem cells (hiPSCs)-based AD models, and conditional knock-out mice for this study. See Working Model (Fig. 2).

Lab Members

Raja Bhattacharyya
Principal Investigator

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

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, his research shows that sigma-1 receptors (S1R) play a significant role in regulating MAM assemblies and generating Abeta 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 Abeta generation in axons and synapses.

Dr. Bhattacharyya’s current research focuses on understanding the S1R-MAM axis in AD pathology, specifically focusing on the role of MAM thickness or gap width in regulating neuronal versus axonal Abeta levels in pathogenic conditions.  This research carries major implications for developing novel AD therapies based on targeting S1R-MAM pathway 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 RIN3, in regulating endocytosis and endosomal homeostasis in AD development. In an in vitro study, he reported that the neuronal isoform of BIN1 specifically regulates APP endocytosis in a RIN3-dependent manner, and is now studying the role of BIN1 and RIN3 interaction in the development of AD using 3D neural, hiPSC, and animal models of AD. Dr. Bhattacharyya is also developing therapeutic strategies to lower AD pathogenesis 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. This 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 therapeutics targeting the early- or late-stage pathology of AD.

View Dr. Bhattacharyya's Harvard Catalyst profile

Recent Publications

1. Bhattacharyya R, Barren C, Kovacs DM. Palmitoylation of amyloid precursor protein regulates amyloidogenic processing in lipid rafts. J Neurosci. 2013;33(27):11169-83. doi: 10.1523/JNEUROSCI.4704-12.2013. PubMed PMID: 23825420; PMCID: PMC3718372.
2. Bhattacharyya R, Black SE, Lotlikar MS, Fenn RH, Jorfi M, Kovacs DM, Tanzi RE. Axonal generation of amyloid-beta from palmitoylated APP in mitochondria-associated endoplasmic reticulum membranes. Cell Rep. 2021;35(7):109134. doi: 10.1016/j.celrep.2021.109134. PubMed PMID: 34010653; PMCID: PMC8287518.
3. Bhattacharyya R, Fenn RH, Barren C, Tanzi RE, Kovacs DM. Palmitoylated APP Forms Dimers, Cleaved by BACE1. PLoS One. 2016;11(11):e0166400. doi: 10.1371/journal.pone.0166400. PubMed PMID: 27875558; PMCID: PMC5119739.
4. Bhattacharyya R, Teves CAF, Long A, Hofert M, Tanzi RE. The neuronal-specific isoform of BIN1 regulates beta-secretase cleavage of APP and Abeta generation in a RIN3-dependent manner. Sci Rep. 2022;12(1):3486. Epub 20220303. doi: 10.1038/s41598-022-07372-4. PubMed PMID: 35241726; PMCID: PMC8894474
5. Lotlikar MS, Tarantino MB, Jorfi M, Kovacs DM, Tanzi RE, Bhattacharyya R. Microfluidic separation of axonal and somal compartments of neural progenitor cells differentiated in a 3D matrix. STAR Protoc. 2022;3(1):101028. Epub 20220107. doi: 10.1016/j.xpro.2021.101028. PubMed PMID: 35059649; PMCID: PMC8755568.
6. Jacob C. Zellmer LS, Rudolph E. Tanzi , and Raja Bhattacharyya. Quantitative Analysis of Mitochondria-Associated ER Membrane (MAM) Stabilization in a Neural Model of Alzheimer’s Disease (AD). Journal of Visualized Experiments. 2024 (accepted)

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