Inhibition of RTN3 aggregation as a novel therapeutic target to reduce cognitive failure in AD
MentorRiqiang Yan, PhD The Cleveland Clinic Foundation
This study hypothesizes that aggregation of a BACE inhibitor (RTN3) may lead to increased levels of amyloid beta. By defining a class of potential inhibitors of RTN3 aggregation, this proposal seeks to determine a new class of therapeutic interventions against Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly affecting over 5 million Americans. Unfortunately despite extensive research there is no effective treatment for this disease up to today. Hence, every approach that will help to alleviate cognitive dysfunction in AD patients deserves through investigation. A protein called reticulon 3 (RTN3) has recently been found to be accumulated in the brains of AD patients in a distinct population of damaged neurons that cannot be seen in non-demented brains. This accumulation of RTN3 in AD brains leads to the formation of RTN3 aggregation and the extent of aggregation correlates with the cognitive decline as revealed in our animal study. We hypothesize that inhibition of RTN3 aggregation will block the formation of neuronal dystrophy and reduce amyloid deposition, offering a new therapeutic target in AD. A biochemical assay has been developed in our laboratory to monitor the accumulation of RTN3 in cells and this assay has identified a compound that can effectively inhibit the accumulation of RTN3. Our overall aim is to determine the potential therapeutic application of the inhibitor in reducing cognitive failure in AD animal models. Inhibition of the formation of these RTN3 damaged neurons and improved cognitive performance in animal models may lead to human clinical trials. In specific aim 1 we will further characterize how the compound inhibits accumulation of RTN3 by using structure activity studies. In specific aim 2 we will take advantage of our ability to detect biochemically tractable accumulated RTN3 to study the in vivo effect of this inhibitor of RTN3 accumulation on the formation of RTN3 damaged neurons using mice that express higher levels of RTN3, produce RTN3 accumulation and RTN3 damaged neurons and mice, which produce age related neuritic plaques containing the toxic amyloid peptide.