Translational Vision and Neuroscience Research Panel ; Alzheimer's disease is a common affliction that disrupts the lives of millions and costs the country hundreds of millions of dollars. The federal government, state governments, philanthropic foundations, and industry have all committed resources to solving the Alzheimer's disease problem. Clinical and basic science investigators with a wide range of backgrounds have dedicated themselves to this disease. This talk will review the current state of Alzheimer's disease research and discuss where we stand in terms of a cure. This talk will try to predict where Alzheimer's disease research will go in the near future by considering where it's been in the recent past.
Service members during military actions or combat training are frequently exposed to primary blasts by weaponry. Most studies have investigated moderate or severe brain injuries from blasts generating overpressures >100 kPa, whereas understanding the pathophysiology of low-intensity blast (LIB)-induced mild traumatic brain injury (mTBI) leading to neurological deficits remains elusive. Our recent studies, using an open-field LIB-induced mTBI mouse model with a peak overpressure at 46.6 kPa, demonstrated behavioral impairments and brain nanoscale damages, notably mitochondrial and axonal ultrastructural changes. In this study, we used tandem mass tagged (TMT) quantitative proteomics and bioinformatics analysis to seek insights into the molecular mechanisms underlying ultrastructural pathology. Changes in global- and phospho-proteomes were determined at 3 and 24 h and at 7 and 30 days post injury (DPI), in order to investigate the biochemical and molecular correlates of mitochondrial dysfunction. Results showed striking dynamic changes in a total of 2216 proteins and 459 phosphorylated proteins at vary time points after blast. Disruption of key canonical pathways included evidence of mitochondrial dysfunction, oxidative stress, axonal/cytoskeletal/synaptic dysregulation, and neurodegeneration. Bioinformatic analysis identified blast-induced trends in networks related to cellular growth/development/movement/assembly and cell-to-cell signaling interactions. With observations of proteomic changes, we found LIB-induced oxidative stress associated with mitochondrial dysfunction mainly at 7 and 30 DPI. These dysfunctions included impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated respiration-relevant enzyme activities. Insights on the early pathogenesis of primary LIB-induced brain damage provide a template for further characterization of its chronic effects, identification of potential biomarkers, and targets for intervention.
