The purpose of the proposed project is to assess if genetic and pharmacological manipulations that increase lifespan will similarly delay the onset of pathologies in models of Alzheimer's Disease (AD), with the ultimate goal of developing better treatments for this devastating and expensive disease. There are currently no effective treatments for this disease, which is on course to bankrupt the American health system in less than 30 years, despite tremendous and expensive efforts by pharmaceutical companies. The proposed studies take a different approach than taken by pharmaceutical companies, which have been based on specific targets. Instead the proposed studies, in response to NIH PAR-18-596, is based on the concept that since age is the major risk factor for AD, and genes that produce AD in humans produce pathologies in model organisms whose time-course scales with lifespan, manipulations that increase lifespan might also delay the onset of AD in humans. Indeed we and others have already demonstrated that some genetic manipulations and drugs that increase lifespan in the model organ C. elegans also delay symptoms in a standard transgenic model of AD, and some of these discoveries have led to current clinical trials in human AD. However, only a very small fraction of manipulations known to increase lifespan have been assessed for their effects on impairments in models of AD. We therefore propose to address this deficiency by assessing effects of genetic and pharmacological manipulations that reliably increase lifespan on three different C. elegans models of AD: muscle-specific human Abeta 1-42 (standard model), and neuronal-specific human Abeta and Tau, both implicated in human AD. We will also conversely assess if drugs we have already discovered to protect in the muscle-specific Abeta model will also protect in the neuron- specific models of AD and to increase lifespan. Based on the success of the small number of similar studies which we and others have carried out, leading to clinical trials in human AD, we anticipate that the presently proposed studies will vastly increase the available drugs and drug targets promising to treat human AD.
Alzheimer's Disease is one of the greatest threats to public health and public finances in the US. Despite tremendous investment by the drug industry targeting specific molecules, no effective treatments are available. The present proposal uses a different approach, exploiting the link between aging and Alzheimer's Disease, which we anticipate will lead to a vast increase in the number of targets and drugs available for clinical trials for the disease.
