Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-␤ (A␤) plaques in the frontal cortex (38%; p ϭ 0.018), the cortex at the level of the hippocampus (53%; p ϭ 0.0003), and the hippocampus (40%; p ϭ 0.06). This was associated with decreased cortical A␤1-40 (35%; p ϭ 0.005) and A␤1-42 (22%; p ϭ 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for ␣-Cterminal fragment (␣-CTF), 54% and p ϭ 0.04; for ␤-CTF, 35% and p ϭ 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant ( p Ͻ 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.

In both HIVE and AD, blood-borne activated monocyte/macrophages and lymphocytes appear to migrate through a disrupted blood-brain barrier. The lacunae around macrophages in amyloid-beta plaques but not in vessel walls are consistent with the ability of macrophages to phagocytize and clear amyloid-beta deposits in vitro.

Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development of novel treatments targeting AQP4 to reduce edema could lessen the neuropathologic sequelae. We hypothesized that inhibiting AQP4 expression by injection of small-interfering RNA (siRNA) targeting AQP4 (siAQP4) after juvenile TBI would decrease edema formation, neuroinflammation, neuronal cell death, and improve neurologic outcomes. The siAQP4 or a RNA-induced silencing complex (RISC)-free control siRNA (siGLO) was injected lateral to the trauma site after controlled cortical impact in postnatal day 17 rats. Magnetic resonance imaging, neurologic testing, and immunohistochemistry were performed to assess outcomes. Pups treated with siAQP4 showed acute (3 days after injury) improvements in motor function and in spatial memory at long term (60 days after injury) compared with siGLO-treated animals. These improvements were associated with decreased edema formation, increased microglial activation, decreased blood-brain barrier disruption, reduced astrogliosis and neuronal cell death. The effectiveness of our treatment paradigm was associated with a 30% decrease in AQP4 expression at the injection site.

Traumatic brain injury (TBI) is one of the leading causes of death and disability in children and adolescents. The neuropathological sequelae that result from TBI are a complex cascade of events including edema formation, which occurs more frequently in the pediatric than the adult population. This developmental difference in the response to injury may be related to higher water content in the young brain and also to molecular mechanisms regulating water homeostasis. Aquaporins (AQPs) provide a unique opportunity to examine the mechanisms underlying water mobility, which remain poorly understood in the juvenile post-traumatic edema process. We examined the spatiotemporal expression pattern of principal brain AQPs (AQP1, 4, and 9) after juvenile TBI (jTBI) related to edema formation and resolution observed using magnetic resonance imaging (MRI). Using a controlled cortical impact in post-natal 17 day-old rats as a model of jTBI, neuroimaging analysis showed a global decrease in water mobility (apparent diffusion coefficient, ADC) and an increase in edema (T2-values) at 1 day post-injury, which normalized by 3 days. Immunohistochemical analysis of AQP4 in perivascular astrocyte endfeet was increased in the lesion at 3 and 7 days post-injury as edema resolved. In contrast, AQP1 levels distant from the injury site were increased at 7, 30, and 60 days within septal neurons but did not correlate with changes in edema formation. Group differences were not observed for AQP9. Overall, our observations confirm that astrocytic AQP4 plays a more central role than AQP1 or AQP9 during the edema process in the young brain.

Traumatic brain injury (TBI) affects many infants and children, and results in enduring motor and cognitive impairments with accompanying changes in white matter tracts, yet few experimental studies in rodent juvenile models of TBI (jTBI) have examined the timeline and nature of these deficits, histologically and functionally. We used a single controlled cortical impact (CCI) injury to the parietal cortex of rats at post-natal day (P) 17 to evaluate behavioral alterations, injury volume, and morphological and molecular changes in gray and white matter, with accompanying measures of electrophysiological function. At 60 days post-injury (dpi), we found that jTBI animals displayed behavioral deficits in foot-fault and rotarod tests, along with a left turn bias throughout their early developmental stages and into adulthood. In addition, anxiety-like behaviors on the zero maze emerged in jTBI animals at 60 dpi. The final lesion constituted only *3% of brain volume, and morphological tissue changes were evaluated using MRI, as well as immunohistochemistry for neuronal nuclei (NeuN), myelin basic protein (MBP), neurofilament-200 (NF200), and oligodendrocytes (CNPase). White matter morphological changes were associated with a global increase in MBP immunostaining and reduced compound action potential amplitudes at 60 dpi. These results suggest that brain injury early in life can induce long-term white matter dysfunction, occurring in parallel with the delayed development and persistence of behavioral deficits, thus modeling clinical and longitudinal TBI observations.