Alzheimer’s Disease Protection by Reduced Adenylyl Cyclase Type 5

通过减少 5 型腺苷酸环化酶来预防阿尔茨海默病

• 批准号: 10526756
• 负责人: M. Maral Mouradian
• 金额: $ 43.18万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526756
• 关键词: Address; Adenylate Cyclase; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Apoptosis; Applications Grants; Behavioral; Biochemical; Brain; Cell Survival; Cerebrovascular Circulation; Cyclic AMP; Data; Dementia; Deposition; Development; Diabetes Mellitus; Disease; Exercise; Exhibits; Future; Glucose; Health; Heart failure; Human Amyloid Precursor Protein; Impaired cognition; Insulin Resistance; J20 mouse; Knock-out; Knockout Mice; Laboratories; Lead; Longevity; Mammals; Memory; Memory Loss; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Motor; Mus; Obesity; Organ; Organism; Oxidative Stress; Pathogenesis; Pathology; Patients; Performance; Phenotype; Play; Population; Positioning Attribute; Prevalence; Protein Isoforms; Receptor Signaling; Research; Role; Senile Plaques; Signal Transduction; Synapses; Testing; Transgenic Animals; Wild Type Mouse; Yeasts; adenylyl cyclase type V; aging brain; aging population; beta-adrenergic receptor; biological adaptation to stress; exercise capacity; glucose tolerance; improved; indexing; inhibitor; insulin tolerance; mitochondrial dysfunction; mutant; neurofilament; neuroinflammation; new therapeutic target; novel; overexpression; protective effect; response; small molecule; therapeutic evaluation; therapeutic target; virtual

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.

项目总结: