Our laboratory is investigating the mechanism of memory disruption and synaptic dysfunction in Alzheimer’s Disease. We use a combination of cell culture and transgenic animal approaches in an attempt to understand why the overexpression of the amyloid precursor protein (APP) or direct application of its active peptide, A-beta, inhibits intracellular signaling in neuronal cells and leads to alterations of electrical activity, dendritic spine morphology and behavior.  These results are extended with analyses of neurons taken from post-mortem Alzheimer’s Disease brains.  In the past two years our attention has been on the PKA-CREB signaling pathway and on the role of ubiquitin c-terminal hydrolase-L1 (Uch-L1) in regulating these events. We have used both drugs and protein transduction techniques to show that A-beta induced changes, both in culture and in the animal, can be reversed by restoring these pathways to their normal “balance”. Other projects involve the induction of  neurogenesis in neural stem cells by A-beta raising the possibility of an endogenous repair mechanism in AD, and the analysis of the action of the ginkgolides on neuronal function. The laboratory approaches these questions with a wide range of tools including biochemistry, cell biology, physiology and microscopy.

Selected Recent Publications:

• Vitolo, O.V., Sant’Angelo, A., Costanzo, V., Battaglia, F., Arancio, O and Shelanski, M.L., 2002. Amyloid b-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. (U.S.) 99:13271-74

• Troy, C. M. and M. L. Shelanski (2003). "Caspase-2 redux." Cell Death Differ 10(1): 101-7.

• Lopez-Toledano, M. A. and M. L. Shelanski (2004). "Neurogenic effect of beta-amyloid peptide in the development of neural stem cells." J Neurosci 24(23): 5439-44.

• Moolman, D. L., O. V. Vitolo, Vonsattel, J-P, and Shelanski, M.L.. (2004). "Dendrite and dendritic spine alterations in alzheimer models." J Neurocytol 33(3): 377-87.

• Rabacchi, S. A., W. J. Friedman, Shelanski, M.L. and Troy, C.M.. (2004). "Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein." Neurobiol Aging 25(8): 1057-66.

• Gong, B, Vitolo, O,  Trinchese, F., Liu, S., Shelanski, M.L.  and Arancio, O (2004) Persistent Improvement in Synaptic and Cognitive Functions in an  Alzheimer Mouse Model Following Rolipram Treatment,  J. Clin. Invest. 114:1624-1634.

• Davidson, T. J., Harel, S., Arboleda, V. A., Shelanski, M. L., Greene, L. A. and Troy, C. M. (2004) Highly efficient siRNA delivery to primary mammalian neurons induces microRNA-like effects before mRNA degradation J. Neurosci 24:10040-10046.

• Gong,B., Cao, Z., Zheng, P., Vitolo, O.V., Liu, S., Staniszewski, A., Moolman D., Zhang, H., Shelanski, M.L. and Arancio, (2006) O., Uch-L1 is a Downstream Regulator of Synaptic Function and Contextual Memory following Amyloid Elevation, Cell 126:775-788