Taub Institute: Genomics Core


Columbia University
Irving Medical Center
Neurological Institute

710 West 168th Street, 3rd floor
(212) 305-1818

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About Us

Taub Faculty

Roger Lefort, PhD

Roger Lefort, PhD

Assistant Professor of Pathology & Cell Biology

Email: rl2040@cumc.columbia.edu
Tel: 212-305-2783

Research Summary:

Molecular mechanisms of neurodegeneration and synaptotoxicity in Alzheimer's disease

Synaptic dysfunction and the loss of dendritic spines are invariable occurrences in Alzheimer's disease (AD). The focus in our lab is to elucidate the molecular mechanism(s) by which synapses are abnormally pruned in the disease. Our research has implicated the Rho-family GTPases, RhoA and Rac1, as key mediator of the synaptotoxic effects of Abeta in neurons. RhoA and Rac1 play critical roles in regulating dendritic spines dynamics by regulating the actin cytoskeleton. RhoA and Rac1 have antagonistic effects: Rac1 favors the formation and stabilization of new spines, whereas RhoA blocks their sprouting and promotes their destabilization.

This implies that an imbalance in RhoA/Rac1 signaling may have deleterious effects on dendritic maintenance. Consistent with this idea, our studies show that spine loss in neurons exposed to A╬▓ correlates with increased RhoA and decreased Rac1 activity. Moreover, blocking RhoA activity neurons completely abrogates the synaptotoxic effects of A╬▓ suggesting that RhoA may be a therapeutic target for AD. We are actively investigating this possibility through a series of studies using a combination of molecular biological, cellular, and mouse genetic approaches.

In a second related project we are characterizing molecules and receptors that play important roles in Abeta signaling, leading to neurodegeneration and/or synaptic dysfunction with a specific focus on Ephrin and APP signaling. Interestingly, recent GWAS studies have identified EphA1 as a risk factor for AD, through a mechanism that has yet to be explored. We are using molecular biological tools to investigate the mechanism by which such intrinsic signals mediate the effects of Abeta in pyramidal neurons.

Current Projects:

- APP dimerization in Alzheimer's disease
- Dysregulation of ephrin signaling in synaptic dysfunction

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