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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029802-05
Application #
8084139
Study Section
Special Emphasis Panel (ZRG1-ICP2-B (50))
Program Officer
Buckholtz, Neil
Project Start
2007-09-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$126,758
Indirect Cost
Name
University of California Santa Barbara
Department
Neurosciences
Type
Organized Research Units
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
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
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
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
Sandoval-Hernández, Adrián G; Buitrago, Luna; Moreno, Herman et al. (2015) Role of Liver X Receptor in AD Pathophysiology. PLoS One 10:e0145467
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
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
Lopez-Tobon, Alejandro; Castro-Alvarez, John Fredy; Piedrahita, Diego et al. (2011) Silencing of CDK5 as potential therapy for Alzheimer's disease. Rev Neurosci 22:143-52

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