The complex role of nadph-oxidase in alzheimer's disease

The mechanisms involved in the pathology underlying the progression of Alzheimer’s disease (AD) are complicated and involve a variety of cellular and molecular events. The failure to maintain adequate numbers of synapses in key cortical structures is one of the hallmarks of the disease and closely associates with the individual’s cognitive ability. Several studies have linked oxidative stress to this loss of synaptic plasticity. NADPH-oxidase (NOX) appears to be a major source of oxidative stress and has been shown to be significantly upregulated early in the disease process. While NOX derived reactive oxygen species (ROS) are required for neuronal signaling, memory, and vascular function, its overproduction has been linked to several neuropathological mechanisms leading to behavioral changes in AD. We have recently shown a close association between the levels of NOX in both the frontal and temporal cortex and the individual’s score on the mini mental state exam. Recent studies have also linked oxidative stress with cytoskeletal pathology. Recent studies have shown that the actin binding protein, cofilin, is increased in AD. Activated cofilin has the ability to modulate the dendritic spine and directly influence synaptic plasticity. Oxidative stress has been shown to alter the levels of activated cofilin. The central hypothesis of this grant is that the progressive decline in cognitive function in AD is the result of a failure to maintain adequate numbers of synapses which is directly related to the levels of oxidative stress and cytoskeletal changes within the neuron. If the loss of synaptic plasticity leads to the progressive loss of cognitive function, then a key question to be answered is what region of the brain is affected early in AD. The ventral medial temporal lobe (vMTL) is an area believed to be affected early in AD. The proposed experiments will evaluate changes in this region in three different groups: no cognitive impairment (NCI), preclinical AD (PCAD) and amnestic MCI (aMCI). The vMTL will be evaluated for changes in NOX, synaptic proteins and cofilin.