Aging is the greatest single risk factor for Alzheimer’s disease (AD) and AD-related diseases (ADRD). A diagnosis of AD/ADRD reflects the progressive loss of memory, speech processing and visual/spatial abilities as the brain deteriorates. People with AD/ADRD lose independence, and the loss of neurons leads to death as the brain loses the ability to regulate bodily functions. Treatment options for people diagnosed with AD/ADRD are limited and can have serious side effects. This is a significant problem, as lower rates of births and higher life expectancy continues to transform the age structure of the US population, increasing the proportion of people with advanced age (>65yr) and the number of people being diagnosed with AD/ADRD. The small, secreted peptide adropin is a new lead for developing treatments for neurodegenerative conditions underlying dementia. In adults aged 70 years or older, low circulating adropin concentrations associate with accelerated cognitive decline. While the source of circulating adropin is not known, it is very highly expressed in the human nervous system. Adropin expression in brain tissues shows strong, positive correlations with gene networks that are involved in mitochondrial and neuronal functions, suggesting a link between adropin and how the brain uses energy. Preclinical studies using mouse models suggest that reversing a decline in adropin expression with natural aging delays or prevents mild cognitive impairment. This proposal address two critical gaps in knowledge. First, whether low adropin levels are sufficient to accelerate cognitive decline is not known. Second, whether the peptide is effective in severe mouse models of neurodegeneration has not been studied. AIM 1 determines whether low adropin expression accelerates aging-related cognitive decline and neurodegeneration. Cognitive functions of adropin-deficient mice will be compared to wild-type controls up to 18 months of age (corresponding to a human age of 56-69 years) using tests of spatial learning and memory. Biochemical signatures of inflammation, mitochondrial and synaptic dysfunctions will also be assessed. AIM 2 determines whether administration of synthetic adropin peptide to SAMP8 mice prevents or reverses cognitive impairment. SAMP8 mice exhibit many of the brain pathologies considered as ‘classical’ age-related and develop severe brain inflammation, cognitive deficits, and behavioral changes around 12 months of age. The hypothesis that adropin will improve cognition in this model of accelerated neurodegeneration is supported by strong preliminary data showing reversal of cognitive impairment in 12-month-old SAMP8 mice treated for 2 weeks with the peptide. The impact of treatment on neurochemical signatures of inflammation, mitochondrial and synaptic functions will also be assessed. The results from these experiments will provide critical preclinical data that will inform future studies of the role of this novel, important neuropeptide in r...