Alzheimer's Disease is associated with metabolic dysfunction, glucose and insulin resistance, oxidative stress,mitochondrial dysfunction, and reduced exercise capacity. Oxidative stress and mitochondrial dysfunctioncorrelate with the development of beta-amyloid (Aβ) deposits, one of the hallmarks of AD that begin years beforethe onset of memory and cognitive decline. Moreover, patients with AD have a reduced lifespan. Accordingly, itwould be beneficial to examine novel models of healthful longevity with enhanced metabolism, glucose andinsulin tolerance, exercise capacity, and protection against oxidative stress, mitochondrial dysfunction, andapoptosis. All these features are present in the adenylyl cyclase type 5 (AC5) knock out (KO) mouse, whichexhibits healthful longevity, associated with all major molecular factors that protect against AD. Adenylyl cyclase(AC) induces cyclic AMP (cAMP) and, therefore, regulates sympathetic control and β-adrenergic receptor (β-AR) signaling, and is thus a key regulator of health and longevity in organisms ranging from yeast to mammals.AC5 is one of ten AC isoforms and is expressed in virtually every organ in the body, including the brain. Insupport of its role in aging, we have found that disruption of AC5 (AC5 KO) promotes healthful longevity,enhances exercise performance and protects against diabetes and heart failure, all of which should be helpfulin protecting against Alzheimer's Disease. Our preliminary data also show that AC5 KO mice perform better onmemory and motor tasks compared to wild-type mice. In contrast, the Alzheimer model J20 mice, a transgenicanimal that overexpresses mutant human amyloid precursor protein (APP), exhibits memory loss as expected.A pharmacological inhibitor of AC5 is the goal for clinical translation. We have developed a pharmacologicalinhibitor of AC5, which is known as C90, as the lead candidate for the inhibition of AC5 targeting myocardialischemia. C90 leads to robust inhibition of AC5, has high solubility and readily absorbed orally. It showed efficacyin animal models of exercise and myocardial ischemia. The main drawback with C90 is the presence of ahydroxamic acid group. Hydroxamates are associated with adverse effects and are often mutagenic. Themutagenicity of the hydroxamate group is proposed be due to its rearrangement to isocyanate which act asalkylating agents of DNA. The goal of this application is to design and synthesize a novel C90 that would retainthe biological activity of C90, but devoid of the toxic liability of a hydroxamic acid group.
Public Health Relevance Statement: Project narrative:
This grant application is in response to a need to increase research in Alzheimer's Disease, which is the most
common form of dementia with a prevalence that is expected to quadruple by 2050 as the world population
ages rapidly. This proposal will investigate a novel therapeutic target, i.e., inhibition of type 5 adenylyl cyclase,
which extends longevity, improves exercise capacity and protects against diabetes and obesity, all critical to
the health of the aging population, in general, and Alzheimer's Disease patients, in particular.
Project Terms: <3'5'-cyclic ester of AMP><3,5 cyclic AMP synthetase><β-adrenergic receptor> | | 