Alzheimer’s Disease Protection by Reduced Adenylyl Cyclase Type 5

项目总结:

Project Summary: Alzheimer’s Disease (AD) is associated with metabolic dysfunction, glucose and insulin resistance, oxidative stress, mitochondrial dysfunction, and reduced exercise capacity. Oxidative stress and mitochondrial dysfunction correlate with the development of beta-amyloid (Aβ) deposits, one of the hallmarks of AD that begin years before the onset of memory and cognitive decline. Moreover, patients with AD have a reduced lifespan. Accordingly, it would be beneficial to examine novel models of healthful longevity with enhanced metabolism, glucose and insulin tolerance, exercise capacity, and protection against oxidative stress, mitochondrial dysfunction, and apoptosis. All these features are present in the adenylyl cyclase type 5 (AC5) knock out (KO) mouse, which exhibits 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. In support 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 helpful in protecting against AD. Our preliminary data also show that AC5 KO mice perform better on memory and motor tasks compared to wild-type mice. In contrast, the Alzheimer model J20 mice, a transgenic animal that overexpresses mutant human amyloid precursor protein (APP), exhibits memory loss as expected. We hypothesize that the AC5 KO mouse and the brain-specific AC5 KO mice (AC5 BKO) are models for protection against AD and that J20 mice lacking AC5 will be protected from amyloid Aβ related pathology. The first specific aim will determine whether AC5 plays a role in AD-related pathology and whether deleting it mitigates the J20 phenotype. And the second specific aim will determine whether the enhanced performance of AC5 KO mice is due to its systemic actions or whether selective deletion of AC5 in the brain is sufficient to have a beneficial effect on AD-like phenotype. Importantly, all mouse lines needed to address these questions are available to us for study.