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Rethinking Alzheimer´s disease therapeutics: Synapses as prime targets

CMCB external seminar

Date:24.05.2018, 16:00 - 17:00
Speaker: Prof. Roger Lefort, Columbia University Medical Center. Department of Pathology and Cell Biology, The Taub Institute for Research on Alzheimer's Disease and the Aging Brain
Location: CRTD, ground floor, auditorium left

Abstract:

Synaptic dysfunction and the loss of dendritic spines are invariable occurrences in Alzheimer’s disease (AD). 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.

5 most important publications:

Olabarria M, Corona C, Pasini S, Lefort R; Topoisomerase inhibitor type I topotecan reverses memory impairments in Alzheimer’s disease mouse model. J. Clin. Invest. (in review)

Olabarria M, Corona C, Robador P, Pasini S, Song C, Patel H, Lefort R; Dysfunction of the ubiquitin E3 ligase Ube3A/E6-AP contributes to synaptic pathophysiology in Alzheimer’s disease. Comm. Biol. (in press)

Yang J, Mandriota N, Harrellson SG, Molina JA, Yuste R, Lefort R., Sahin O., Synaptic elasticity. Nat. Neurosci. (in press)

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

†Pianu B., †Lefort R., Thuiliere L., Tabourier E., Bartolini F.; Amyloid beta1-42 peptide regulates microtubule stability independently of tau. J Cell Sci. 2014 Mar 1:127(Pt 5):1117-27

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