A geroscience approach for treating Alzheimer's disease

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Abstract Geroscience is a multidisciplinary field that examines the relationship between biological aging and age-related diseases through multiple processes. These processes are highly integrated with one another such that targeting them as a group may be an effective approach to developing therapies to prevent or delay age- related disease. Alzheimer's disease (AD) is an age-related disease and is expected to increase with the number of elderly individuals rapidly rising in both developed and developing countries. Pharmacological efforts to find disease-modifying treatments have met with limited success possibly because they have focused on identifying a specific drug that targets a specific mechanism. AD is a complex disease involving numerous mechanisms in line with processes of biological aging. Therefore, a geroscience approach to successfully treating AD is a logical pharmacological concept. A cocktail of three repurpose drugs has been selected for testing in this proposal based on established anti-aging effects in mice. Phenylbutyrate downregulates the unfolded protein response and inhibits histone deacetylase thereby upregulating anti-inflammatory molecules. Rapamycin inhibits mTOR, enhances vascular endothelial cell function and activates autophagy. Acarbose acts as a caloric restriction mimetic to enhance mitochondrial efficiency and suppress oxidative stress. The hypothesis is that a drug cocktail of rapamycin, acarbose, and phenylbutyrate, that targets multiple aging processes associated with Alzheimer's disease will alleviate cognitive dysfunction and neurological pathology in an aging AD mouse model. Aim 1 will determine if a slowdown in aging will slow down the development of early stage AD dementia and neurological lesions using the 3-drug cocktail in 20- month old AAV Aβ42/P301Ltau mice. The contribution of the cocktail will be evaluated in relation to bioavailability, suppression of systemic disease, alleviation of cognitive impairment and other clinical and pathological features, and lack of toxicity. Aim 2 will investigate aging processes that can increase the risk for developing AD, focusing on inflammation, autophagy impairment, insulin/mitochondrial dysfunction and oxidative stress, epigenetic dysfunction, and vascular impairment. Aim 3 will develop a molecular bridge for Aims 1 and 2 studies as a unique metabolomics way of showing the relationship between phenotype and processes of aging. Metabolomic profiles will be developed in brain and liver from Aim 1 cohorts. There will also be an opportunity to assess effect of gender, age, and strain on metabolomics outcomes. The concept of a geroscience drug cocktail that could successfully alleviate AD would be expected to have a significant impact on the health of patients suffering from early symptoms of dementia and other AD related issues.