Laboratory of Ana Griciuc, PhD
Email: griciuc.ana@mgh.harvard.edu
Overview
Genetic studies of Alzheimer’s disease (AD) have revealed the AD-associated genes CD33 and TREM2, which are innate immune receptors expressed on microglia, monocytes, and peripheral macrophages. Dr. Griciuc’s research projects focus on investigating the function of CD33 and TREM2, and how mutations in these genes contribute to AD pathogenesis. To characterize the roles of CD33 and TREM2 mutations in AD, Dr. Griciuc’s team has been using humanized CD33 and Trem2 knock-in mouse models, neuropathology, animal behavior analysis, single-cell RNA-seq, iPSC-derived human microglia-like cells (iMGLs), CRISPR/cas9 gene editing, and microglial cell-based functional assays. Dr. Griciuc also develops viral and non-viral gene therapy strategies targeting CD33 and TREM2 to reduce neuroinflammation and implemented preclinical drug discovery studies based on modulation of microglial activation state.
Research Projects
Role of CD33 and TREM2 mutations in modulating microglial pathology in Alzheimer’s disease
We have been investigating the effects of AD-associated TREM2 gain-of-function and loss-of-function mutations on AD pathogenesis and exploring the underlying molecular mechanisms by using Trem2 knock-in mouse models and iMGLs. To assess the impact of mutations in the ligand-binding domain of CD33 on amyloid beta pathology and neuroinflammation, we have been characterizing iMGLs and humanized mouse models that express either common variant or mutant CD33 crossed to 5xFAD mice. The comprehensive analysis of CD33 and TREM2 mutations will allow us to elucidate the role of these innate immune receptors in AD. This research will also provide a better understanding of how genetic risk factors, CD33 and TREM2, translate into cellular dysfunction in AD, opening new avenues for precision medicine approaches.
Precision gene therapy targeting microglia to modulate neuroinflammation
TREM2 has become a key therapeutic target in Alzheimer’s drug development, with multiple companies pursuing TREM2-activating antibodies and small molecule TREM2 agonists. Currently, CD33 is also one of the most targeted AD genes in the pharmaceutical industry, with companies now developing CD33-inhibiting antibodies and CD33-targeting anti-sense oligonucleotides. Although efforts are underway to develop potent TREM2 activators and CD33 inhibitors, none have yet been clinically validated.
In collaboration with Dr. Casey Maguire at Massachusetts General Hospital, we develop innovative, microglia-targeted adeno-associated virus (AAV) vectors to enable precise genetic manipulation in AD models. Along these lines, we are characterizing novel AAV capsids that mediate transgene delivery to microglia to target CD33 and TREM2 in humanized CD33 and Trem2 mouse models crossed to the 5xFAD mouse model of AD.
In collaboration with Dr. Nitin Joshi at Brigham and Women’s Hospital, we develop and optimize a next-generation lipid nanoparticle (LNP) platform with enhanced brain blood barrier (BBB) penetration, reduced hepatic sequestration, and preferential accumulation in microglia compared to clinically utilized LNP formulations. Our goal is to utilize the optimized LNP platform in therapeutic strategies for AD by enabling minimally invasive, BBB-penetrant delivery of therapeutic RNAs (e.g., mRNA, siRNA) selectively to microglia.
Preclinical drug discovery for Alzheimer’s disease
Through high-throughput screens of libraries comprised of FDA-approved compounds and natural products, we identified hits that increase microglia-mediated uptake of amyloid beta and reduce levels of pro-inflammatory cytokines released by microglia. These compounds maintain microglia in an anti-inflammatory activation state and show great promise in translating our research into novel therapeutics for AD. We validated these hits in dose-dependent assays in iMGLs and are investigating the molecular mechanisms underlying the effects of these compounds on neuroinflammation and microglial cell function.
Research Team
Ana Griciuc, PhD
Principal Investigator, MGH and HMS
Dr. Ana Griciuc is an Assistant Professor of Neurology at Harvard Medical School and Massachusetts General Hospital. She received her Ph.D. degree in Neuroscience from the Helmholtz Research Center Munich and conducted postdoctoral research at Mass General and Harvard Medical School. Within the Genetics and Aging Research Unit, the lab of Dr. Griciuc investigates how mutations in genetics risk factors CD33 and TREM2 contribute to AD pathogenesis, develops gene therapy strategies targeting these innate immune receptors, and performs preclinical drug discovery for AD. Dr. Griciuc has received several awards, including the NIH Pathway to Independence Award, Roger Ackerman Memorial Award, and Excellence in Innovation Award from Mass General Brigham. View Dr. Griciuc’s Harvard Catalyst profile
Dominika Pilat, PhD
Research Fellow, MGH and HMS
Dr. Dominika Pilat, originally from Poland, joined the Griciuc Lab in 2022 as a Research Fellow. She completed her Ph.D. studies at Aix-Marseille University in France, where she explored the role of the membrane metalloproteinase, MT5-MMP, in AD. As a research fellow, Dominika has been investigating the role of TREM2 gain-of-function mutations in AD pathogenesis using mouse models of AD and iPSC-derived human microglia-like cells. Dominika is the recipient of the 2026 Warren Alpert Distinguished Scholar Fellowship Award in Neuroscience. In her free time, she loves running, going to live music shows, reading fiction, or spending the evening watching Bravo. Email: dpilat@mgh.harvard.edu
Eli Abel
Undergraduate Student, MGH and Harvard College
Eli Abel is an undergraduate student in the Griciuc Lab. He is pursuing a Bachelor’s of Arts in Neuroscience at Harvard College and hopes to work as a physician-scientist in the future. In the lab, Eli is characterizing the pathogenetic and immune response properties of CD33 mutations in AD. Outside the lab, Eli loves music, playing piano, viola, and singing in an a cappella group. Email: esabel@mgh.harvard.edu
Ashley Fox
Undergraduate Student, MGH and Harvard College
Ashley is an undergraduate student in the Griciuc Lab. She is pursuing a Bachelor's of Arts in Molecular and Cellular Biology at Harvard College and would like to work as a physician in the future. Her research focuses on investigating the role of TREM2 mutations in regulating microglial function in AD. Outside her academic work, Ashley loves to dance, read, and spend time with her friends and family. Email: ashleyfox@college.harvard.edu
Publications
- Pilat DJ, Le H, Prokopenko D, Lin CJ, Eimer WA, Quinti L, Gavrilles EP, Garcia SN, Heitman SN, ADNI, McGinty D, Cetinbas M, Sadreyev RI, Tanzi RE*, Griciuc A*. The gain-of-function TREM2-T96K mutation increases risk for Alzheimer’s disease by impairing microglial function. Neuron 2026, 114(1):46-66, PMCID: PMC12687738.
- Gao J*, Gunasekar S, Xia ZJ, Shalin K, Jiang C, Chen H, Lee D, Lee S, Pisal ND, Luo JN, Griciuc A*, Karp JM*, Tanzi R*, Joshi N*. Gene therapy for CNS disorders: modalities, delivery and translational challenges. Nat Rev Neurosci 2024; 25(8):553-572.
- Griciuc A, Tanzi RE. The role of innate immune genes in Alzheimer's disease. Curr Opin Neurol 2021; 34(2):228-236, PMCID: PMC7954128.
- Griciuc A, Federico AN, Natasan J, Forte AM, McGinty D, Nguyen H, Volak A, LeRoy S, Gandhi S, Lerner EP, Hudry E, Tanzi RE, Maguire CA. Gene therapy for Alzheimer’s Disease targeting CD33 reduces amyloid beta accumulation and neuroinflammation. Hum Mol Genet 2020; 29(17):2920-2935, PMCID: PMC7566501.
- Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ, Oram MK, Cereghetti G, McGinty D, Anselmo A, Sadreyev RI, Hickman SE, El Khoury J, Colonna M, Tanzi RE. TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer's Disease. Neuron 2019; 103(5):820-835, PMCID: PMC6728215.
Alumni
Postdoctoral research fellows
- Hoang Le, 2017-2023 (now Senior Scientist at GC Therapeutics, Cambridge, MA).
Research technicians
- Danielle McGinty, 2018–2020.
- Sara Heitman, 2021–2023.
- Sheyla Garcia, 2022–2025.
- Nelson Abarca, 2022-2025.