Research Faculty

Address
630 West 168th Street
P&S 15-401
New York, NY 10032

Phone: 212-305-2783
Fax:

rl2040@cumc.columbia.edu
Roger Lefort, Ph.D.
Assistant Professor of Pathology and Cell Biology
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 Aβ correlates with increased RhoA and decreased Rac1 activity. Moreover, blocking RhoA activity neurons completely abrogates the synaptotoxic effects of Aβ 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.
Selected Publications

1. †Pianu B., †Lefort R., Thuiliere L., Taboure E., Bartolini F.; Amyloid beta1-42 peptide regulates microtubule stability independently of tau. J. Cell Sci. (accepted manuscript)

2. †Pozueta J., †Lefort R., Shelanski M.; Synaptic changes in Alzheimer’s disease and its models. Neuroscience 2013 Oct 22; 251:51-65

3. †Pozueta J., †Lefort R., Ribe E.M., Troy, C.M., Arancio O., Shelanski M.; Caspase-2 mediates dendritic spine and behavioral alterations in J20 APP transgenic mice by regulating RhoA activity. Nat. Commun. 2013 Jun 10; 4:1939-50

4. Lefort R., Pozueta J., Shelanski M.; Cross-linking of cell surface APP leads to increased Aβ production in hippocampal neurons: Implications for Alzheimer’s disease. J. Neurosci. 2012 Aug 1; 32(31):10674-85

5. Vitolo O., Gong B., Cao Z., Ishii H., Jaracz S., Nakanishi K., Arancio O., Dzyuba S.V., Lefort R., Shelanski M.; Protection against β-amyloid-induced abnormal function and cell death by Ginkgolide J. Neurobiol. Aging 2009 Feb; 30(2):257-65

Current Projects

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

Committees , Council, and Professional Society Memberships

The New York Academy of Science
Society for Neuroscience
Keywords

Alzheimer’s disease, synapses, ephrin, dendritic spine, RhoGTPase, APP, Abeta


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