Griciuc Lab

Research Overview

Genetic studies of Alzheimer’s disease (AD) have revealed the AD-associated genes CD33 and TREM2, which are innate immune receptors expressed on myeloid cells, including 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 CD33 and Trem2 knock-in mouse models, neuropathology, animal behavior analysis, single-cell RNA-seq, iPSC-derived human microglia-like cells, CRISPR/cas9 gene editing, and microglial cell-based functional assays. Dr. Griciuc also implemented preclinical drug discovery and gene therapy studies for neuroinflammation based on targeting CD33 and modulation of microglial activation state.  

We have been investigating the effects of AD-associated TREM2 gain-of-function mutations on AD pathogenesis and exploring the underlying molecular mechanisms by using TREM2 knock-in mouse models and iPSC-derived human microglia-like cells (iMGLs). To assess the impact of mutations in the ligand-binding domain of CD33 on AD pathogenesis, we have been characterizing humanized mouse models that express either wild-type or mutant CD33 crossed to 5xFAD mice. In collaboration with Dr. Casey Maquire at Massachusetts General Hospital, we are characterizing novel AAV capsids that mediate transgene delivery to microglia to inhibit CD33 function in the humanized wild-type CD33 mouse crossed to the 5xFAD mouse model of AD.

Through high-throughput screens of libraries comprised of FDA-approved compounds and natural products, we identified hits that increase microglia-mediated uptake of Aβ 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 aim to validate our hits in dose-dependent assays in iMGLs and investigate the underlying mechanisms of the effects of these compounds on neuroinflammation and microglial cell function.

Lab Members

Ana Griciuc, PhD
Principal Investigator 

Dr. Griciuc received her M.Sc. in biochemistry from the Max Planck Institute of Neurobiology (Munich) in 2006. As a fellow of the Marie Curie-Neurotrain research training network, she received her Ph.D. in Neuroscience from the Helmholtz Research Center Munich in 2010. During her postdoctoral training at Mass General and Harvard Medical School, Dr. Griciuc showed that CD33 inhibits microglial uptake and clearance of brain amyloid beta (Aβ), a process that requires the ligand-binding domain.

Dr. Griciuc was appointed as Assistant Professor of Neurology at Mass General and Harvard Medical School in 2017. Furthermore, Dr. Griciuc showed that TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer’s disease (AD). She also provided the first proof-of-concept that a gene therapy strategy targeting CD33 can reduce both Aβ accumulation and neuroinflammation in mouse models of AD. Based on these seminal findings, CD33 has emerged as a major drug target in the biopharmaceutical industry.

Dr. Griciuc has received several awards, including the NIH Pathway to Independence Award and Excellence in Innovation Award from Mass General Brigham.

View Dr. Griciuc's Harvard Catalyst profile

Dominika Pilat, PhD
Research Fellow 

Dr. Dominika Pilat, originally from Poland, joined the Neuroinflammation team at the Genetics and Aging Research Unit in May 2022. She completed her Ph.D. studies at Aix-Marseille University in France, where she investigated the role of the membrane metalloproteinase, MT5-MMP, in AD and validated it as a new therapeutic target. Overall, Dominika's research showed that modulation of MT5-MMP may have beneficial consequences at very early stages of the disease, with consequences on synaptic activity. Based on these results, Dominika was the first author on a research article in the Journal of Neuroinflammation (2022). Since joining the unit, she has been investigating the role of TREM2 gain-of-function mutations in AD pathogenesis. For this purpose, Dominika has been using a combination of mouse models of AD, neuropathological assessments, biochemistry, molecular biology, and iPSC-derived human microglia-like cells. In her free time, she loves running, going to live music shows, reading fiction, or simply spending the evening watching Bravo.

Nelson Abarca 
Research Technician 

Sheyla Garcia 
Research Technician 

Recent Publications

1. Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013; 78(4):631-643, PMCID: PMC3706457, selected by Neuron as “Featured Article”
2. 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
3. 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
4. Griciuc A, Tanzi RE. The role of innate immune genes in Alzheimer's disease. Curr Opin Neurol 2021; 34(2):228-236, PMCID: PMC7954128
5. McAlpine CS, Park J, Griciuc A, Kim E, Choi SH, Iwamoto Y, Kiss MG, Christie KA, Vinegoni C, Poller WC, Mindur JE, Chan CT, He S, Janssen H, Wong LP, Downey J, Singh S, Anzai A, Kahles F, Jorfi M, Feruglio PF, Sadreyev RI, Weissleder R, Kleinstiver BP, Nahrendorf M, Tanzi RE, Swirski FK. Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease. Nature 2021; 595(7869):701-706, PMCID: PMC8934148

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