Alzheimer's disease, already a serious global disease afflicting large segments of the population, is about to burgeon into an even larger problem as the baby-boomer bubble approaches retirement age. The disease remains incurable;however validated therapeutic targets are known. RNA interference (RNAi) technology poses a potential therapeutic option which requires further investigation. Targeting the mRNA rather than the protein offers major advantages in the ease of designing a highly specific inhibitory agent and rapidly advancing approaches to RNAi delivery suggest that the method can be developed into a therapy. Our hypothesis is that RNAi will prove to be an effective and selective strategy to slow, and perhaps even reverse, the pathogenic processes in inherited and sporadic AD. This proposal follows the completion of an R21 award of the same title. The announcement for this award was an RFA from the Fogarty Institute for proposals related to Brain Disorders in the Developing World and a major goal of the program was to build research capacity at the foreign site. The successful completion of the R21 aims is described in the preliminary data. The collaborative effort poses two questions concerning the cause and possible treatment of neurofibrillary pathology in AD. One question is whether suppression of Cdk5, an increasingly accepted disease target, can modify neurofibrillary pathology in an animal model. Cdk5 is an enzyme that phosphorylates tau protein and in so doing is thought to contribute to the conversion of the protein into an insoluble aggregate known as the neurofibrillary tangle. Cdk5 will be targeted by RNAi delivered in a viral vector. The second question is whether BACE1 inhibition by RNAi delivery can retard or prevent the development of neurofibrillary pathology in an animal with both plaques and tangles. The studies proposed here are intended to continue building research capacity at the foreign site which is now in a position to launch these studies. In addition to the established collaboration between the Kosik laboratory and the foreign site, two consultants will contribute to capacity building. They are Bev Davidson who will advise on the establishment of a viral core and Frank LaFerla who will contribute the triple transgenic mice to the vivarium at the foreign site.
| Posada-Duque, Rafael Andrés; Ramirez, Omar; Härtel, Steffen et al. (2017) CDK5 downregulation enhances synaptic plasticity. Cell Mol Life Sci 74:153-172 |
| Sabogal-Guáqueta, Angélica Maria; Osorio, Edison; Cardona-Gómez, Gloria Patricia (2016) Linalool reverses neuropathological and behavioral impairments in old triple transgenic Alzheimer's mice. Neuropharmacology 102:111-20 |
| Uribe-Arias, Alejandro; Posada-Duque, Rafael Andrés; González-Billault, Christian et al. (2016) p120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease. J Neurochem 138:624-39 |
| Posada-Duque, Rafael Andres; López-Tobón, Alejandro; Piedrahita, Diego et al. (2015) p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing. J Neurochem 134:354-70 |
| Castro-Alvarez, John Fredy; Uribe-Arias, Alejandro; Cardona-Gómez, Gloria Patricia (2015) Cyclin-Dependent kinase 5 targeting prevents ?-Amyloid aggregation involving glycogen synthase kinase 3? and phosphatases. J Neurosci Res 93:1258-66 |
| Sandoval-Hernández, Adrián G; Buitrago, Luna; Moreno, Herman et al. (2015) Role of Liver X Receptor in AD Pathophysiology. PLoS One 10:e0145467 |
| Sabogal-Guáqueta, Angélica Maria; Muñoz-Manco, Juan Ignacio; Ramírez-Pineda, Jose R et al. (2015) The flavonoid quercetin ameliorates Alzheimer's disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer's disease model mice. Neuropharmacology 93:134-45 |
| Piedrahita, Diego; Castro-Alvarez, John Fredy; Boudreau, Ryan L et al. (2015) ?-Secretase 1's Targeting Reduces Hyperphosphorilated Tau, Implying Autophagy Actors in 3xTg-AD Mice. Front Cell Neurosci 9:498 |
| Lalli, Matthew A; Cox, Hannah C; Arcila, Mary L et al. (2014) Origin of the PSEN1 E280A mutation causing early-onset Alzheimer's disease. Alzheimers Dement 10:S277-S283.e10 |
| Lalli, Matthew A; Garcia, Gloria; Madrigal, Lucia et al. (2012) Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers. Hum Mutat 33:1630-4 |
Showing the most recent 10 out of 12 publications
