Helen & Robert Appel Alzheimer’s Disease Research Institute

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Laboratories

Gan Group

Dr. Gan and team.

The Gan Laboratory

Dr. Li Gan, a neuroscientist internationally acclaimed for her research into neurodegenerative diseases, has been appointed director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine, effective July 1.

The Appel Institute was established in 2006 with a $15 million gift from Helen and Robert Appel, vice chair of the Weill Cornell Medicine Board of Overseers. An integral part of the Feil Family Brain and Mind Research Institute (BMRI) and headquartered in the Belfer Research Building, the Appel Institute is dedicated to understanding the molecular, cellular and genetic underpinnings of Alzheimer’s disease and related degenerative neurological disorders for the benefit of patient care.

Molecular mechanisms in progranulin deficient frontotemporal dementia

Principal Investigator:
Dr. Li Gan

NIH/NIA (09/01/15 – 04/30/20)

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

Principal Investigator:
Dr. Li Gan

NIH/NINDS (09/01/16 – 08/31/21)

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

Principal Investigator:
Dr. Li Gan

NIH/NIA (04/01/17 – 03/31/22)

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

Principal Investigator:
Dr. Li Gan

Rainwater Foundation (08/1/17 – 12/31/18)

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.

Develop therapeutic strategies to enhance protective effects of progranulin

Principal Investigator:
Dr. Li Gan

Bluefield Project to Cure FTD (01/01/18 – 12/31/19)

The aims of this project are to: 1) develop small molecules to restores functional deficits cause by PGRN deficiency in human iPSCs/microglia and 2) determine the PGRN-enhancing effects of engrafted iPSC-derived human microglia in PGRN-deficient mouse models.

Develop iPSC-derived microglia to treat progranulin deficient Frontotemporal Dementia

Principal Investigator:
Dr. Li Gan

California Institute of Regenerative Medicine (12/01/18 – 11/30/20)

The major goals of this project are to: 1) establish and characterize scalable iPSC-derived human microglia overexpressing PGRN; 2) determine the short-term efficacy and safety of the engrafted iPSC-derived human microglia in mouse brains; and 3) determine the long-term efficacy and safety of engrafted iPSC-derived human microglia in PGRN-deficient mouse models.

Functional characterization of Alzheimer’s disease associated genetic variants

Principal Investigator:
Dr. Li Gan, Dr. Yin Shen

UCSF/NIH (09/01/17 – 08/31/22)

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.

Investigating the role of microglia in tau clearance in Alzheimer's disease

Principal Investigator:
Dr. Wenjie Luo, PhD

Coins for Alzheimer's Research Trust (CART)

Stimulating clearance of amyloid plaques and NFTs and reducing the levels of their major components represents attractive therapeutic strategies for treating Alzheimer’s disease. Microglia are the major brain phagocytes that play active and essential roles in innate immune responses, including phagocytosis and degradation. We found that microglia can internalize and degrade the pathological tau proteins. This project focuses on identification and characterization of the cellular pathways and regulatory mechanisms involved in the dynamic of tau metabolism mediated by microglia.

Hsp90-chaperome network in Alzheimer’s disease

Principal Investigator:
Dr. Wenjie Luo, PhD

National Institutes of Health/National Institute on Aging Grant

Neurodegeneration, as occurs in Alzheimer’s disease (AD), is a lengthy multistep process characterized by the accrual of mutant or aberrantly folded proteins and dysregulation of signaling molecules. Heat shock protein 90 (Hsp90) has emerged as the crucial chaperone and mediator of neurodegenerative diseases. We discovered that Hsp90 is required for the stability of mutant tau protein in a tau transgenic mouse model for AD. Inhibition of Hsp90 using a specific small molecule inhibitor attenuates tau aggregation by preventing the association of Hsp90 with tau protein and triggering tau degradation mediated by proteasomes. Collaborating with Dr. Chiosis lab in MSKCC, we are currently investigating the stress-related “epichaperome”, the Hsp90-chaperome networks consisting of multiple chaperone members and their helpers and client proteins, in the brain of AD patients and tau transgenic mice.

Retromer chaperone R33 selectively promotes amyloid degradation by microglia

Principal Investigator:
Dr. Wenjie Luo, PhD

The BrightFocus Foundation

Retromer complex is one of the key regulators of endosomal trafficking. Dysfunction of the retromer complex contributes to amyloidogenesis in AD. The goal of this project is to to characterize a selective effect of pharmacological chaperone for retromer complex (Vps35/Vps29/Vps26) in promoting microglia-mediated Ab degradation without influencing tau clearance.

The functions of the endolysosomal system in the interaction between amyloid plaques and microglia

Principal Investigator:
Dr. Wenjie Luo, PhD

Seed Grants for Cornell Intercampus Collaborative Projects

Emerging evidence suggests that microglia play multiple positive and negative roles in AD, and understanding these activities is of critical importance. Microglia are the main inflammatory cells in the brain, and inflammatory activation can lead to neuronal cell death. We will investigate the cellular and molecular mechanisms by which microglia can digest portions of amyloid plaques and slow their expansion as part of a larger program to understand the activities of microglia associated with AD. A long-term goal is to manipulate microglial properties to enhance protective effects and minimize harmful activities. We plan a closely interacting set of projects to address the roles of microglia in the Alzheimer’s disease (AD) brain, focusing on the endo-lysosomal system.


Weill Cornell Medicine Helen & Robert Appel Alzheimer’s Disease Research Institute 413 East 69th Street New York, NY 10021 Phone: (646-962-4559