The goal of the proposed work is to provide an understanding the role of chronic inflammation in the onset and progression of cognitive decline during aging and Alzheimer's disease. Impaired memory, an early indicator of cognitive decline, is due to impaired synaptic function associated with a redox-mediated hypofunction of N-methyl-D-aspartate receptors (NMDARs). The mechanism involves reactive oxygen species (ROS), possibly from activated microglia, providing a potential link between inflammation and the emergence of impaired memory.
Aim 1 will test the hypothesis that the onset of cognitive decline is influenced by an inflammation induced increase in oxidative stress, resulting in a redox-mediated NMDAR hypofunction. Studies employ sensitive behavioral tests for different cognitive processes, and can detect changes in motor function or motivation. Impaired cognitive function will be related to measures of serum and local brain cytokines, glial activation, oxidativ stress, and redox regulation of NMDAR function. We predict that inflammatory markers in the serum are predictive of the emergence of memory deficits and that for specific neural systems, inflammation markers, and impaired NMDAR function is diagnostic of different cognitive impairment phenotypes. Evidence indicates that decreased NMDAR synaptic activity results in transcriptional changes similar to that associated with age-related cognitive decline and Alzheimer's disease suggesting that a decrease in NMDAR synaptic activity, due to chronic inflammation, alters transcription of neurotrophic, neuroprotective, and synapse specific genes.
Aim 2 examines brain transcription and cognitive decline due to chronic low-level of systemic inflammation. A systemic inflammation model has been developed and involves muscle expression of interleukin-6 (IL-6), which elevates serum IL-6 and induces brain astrogliosis and microglia activation. We predict that a long-term (3 months) increase in serum cytokines will result in a redox-mediated NMDAR hypofunction and a senescent transcription profile.
Aim 3 will examine the idea that region selective upregulation of antioxidant enzymes will have a selective effect in protecting NMDAR function, promoting a youthful transcriptional profile, and rescuing cognition.
Systemic inflammation influences the onset and progression of brain aging, Alzheimer's disease, and other age-related neurodegenerative diseases. The proposed studies will test a hypothesized mechanism that links inflammation induced oxidative stress with synaptic mechanisms that regulate memory and the transcription of genes that maintain the health of neurons.
