Gan Laboratory researchers combine biochemical and functional approaches to dissect the molecular mechanisms of neurodegenerative diseases, including Alzheimer’s and frontotemporal dementia. Using animal and human Induced Pluripotent Stem Cell (IPSC)-derived cellular models, the Gan team explores converging pathways in neurodegenerative diseases, particularly the accumulation and trafficking of toxic proteins and the aberrant activation of innate immune responses. Gan Lab investigators identified new mechanisms by which aberrant signaling in microglia impairs neuronal function, and discovered that Alzheimer’s-associated increases in acetylation of the protein tau mediate tau accumulation and toxicity, leading to two phase-one clinical trials with human patients. They plan to utilize functional genomics to discover novel therapeutic strategies to treat Alzheimer’s disease and frontotemporal dementia.
Li Gan, Ph.D.
Sadaf Amin , Ph.D.
Guillermo Coronas-Samano, MSci.
Li Fan, Ph.D.
Alice Maria Giani, Ph.D.
Shiaoching Gong, Ph.D.
Wenjie Luo, Ph.D.
Eileen Ruth Torres, Ph.D.
Man Ying Wong, M.S.
Mingrui Zhao, Ph.D.
Areas of Investigation
Our laboratory focuses on dissecting the molecular pathways in Alzheimer’s disease (AD) and frontotemporal dementia (FTD), two of the most common dementia in the elderly population. We are intrigued by two interconnected mechanisms that are common to neurodegenerative processes: the accumulation of protein aggregates and miscommunications between neurons and glia, especially microglia. Accumulation of protein aggregates could activate microglia, exacerbating neurodegeneration. On the other hand, microglia could be activated to remove abnormal protein aggregates. We are particularly interested in how aging-related pathways, such as sirtuins, modulate the processes underlying the abnormal accumulation and microglial activation. Our long-term goal is to develop new small-molecule or cell-based approaches to delay or prevent the progression of these devastating aging-associated diseases.
- Do aging-related pathways affect the stability and clearance of protein aggregates in AD and FTD?
- How does aging affect inflammatory and protective function of microglia
- Can we generate patients-specific microglia to remove abnormal protein aggregates?
- What are the roles of aging-associated epigenetic modification in neuronal injury and inflammatory responses?
Our lab aims at dissecting molecular mechanisms and developing novel therapeutic strategies for neurodegenerative diseases, in particular Alzheimer’s disease (AD) and frontotemporal dementia (FTD). We focus on three interconnected mechanisms underlying neurodegeneration.
- Found that cathepsin B (CatB) degrades the protein amyloid ß (Aß) via a unique catabolic mechanism. Accumulation of Aß, the key pathogen in AD, results from an imbalance of production and clearance/degradation.
- Showed that reducing cystatin C (CysC), the endogenous inhibitor of CatB, lowers Aß levels in a CatB-dependent manner, establishing a critical role of CysC-CatB axis in regulating Aß degradation and clearance.
- Discovered that the activation of sirtuins—class III histone deacetylases strongly associated with longevity—protects neurons by block NF-¿B activation in microglia through deacetylation.
- Found that the neural stem cells in the hippocampus of AD mice exhibit abnormal development and impaired functional integration. By combining in vivo labeling, confocal microscopy and electrophysiological recordings, we identified an Aß-induced aberrant neuronal network as the primary mechanism.
- Discovered a new mechanism that contributes to the accumulation of tau, a key pathogen in AD and FTD. We found that tau is acetylated and acetylation blocks the degradation and tau. Moreover, reducing tau acetylation with a small molecule inhibitor leads to depletion of pathogenic phosphorylated-tau in neurons. These findings offer a novel therapeutic direction in AD and related neurodegenerative diseases.
Molecular mechanisms in progranulin deficient frontotemporal dementia
This project aims at investigating mechanisms underlying frontotemporal dementia associated with progranulin deficiency. The aims are to: 1) determine how GRN haploinsufficiency induces endolysosomal dysfunction in human cells; 2) determine the mechanisms by which PGRN deficiency induces hyperactive NF-KB signaling and microglial dysfunction; and 3) determine the mechanisms by which PGRN-deficient microglia induce FTD-related cognitive and circuitry deficits.
Linking tau proteostasis with neuronal activity in FTD
The central goal of this Center Without Walls will be to link the tau proteostasis imbalance with aberrant neuronal activity in FTD. The program aims to discover: 1) what causes tau to accumulate and spread in FTD; 2) how tau proteostasis imbalance induces neuronal dysfunction; and 3) how neuronal activity modulates tau proteostasis.
Tau acetylation in Alzheimer’s Disease
The major goals of this project are to: 1) determine whether aberrant tau acetylation alters tau pathology and distribution in human iPSC neurons; 2) determine whether aberrant ac-tau elevates levels of dendritic tau by destabilizing the AIS in human neurons; and 3) dissect postsynaptic mechanisms underlying tau-mediated impairment in synaptic plasticity and memory encoding.
Stem cell-derived microglia to model and treat tauopathies
The major goals of this project are to: 1) establish and characterize isogenic, inducible, integrated human iPSC-derived microglial cells (i3-MGs); 2) establish an in-vitro tau uptake model in human microglia for drug and functional genomics screening; and 3) establish the engraftment conditions for i3-MGs in tauopathy mice.
Functional characterization of Alzheimer’s disease associated genetic variants
This project will support functional genomic studies to identify causal genetic variations that affect the functions of regulatory regions and therefore predispose for AD. The Gan lab will provide differentiated human iPSCs for genomic analyses and generate CRISPR-edited isogenic lines for 3-5 targeted genes, followed by functional, pathological, and biochemical characterizations.