Obesity is a global pandemic associated with macro- and microvascular endothelial dysfunction. Microvascular endothelial dysfunction has recently emerged as a significant risk factor for the development of cognitive impairment. In this review, we present evidence from clinical and preclinical studies supporting a role for obesity in cognitive impairment. Next, we discuss how obesity-related hyperinsulinemia/insulin resistance, systemic inflammation, and gut dysbiosis lead to cognitive impairment through induction of endothelial dysfunction and disruption of the blood brain barrier. Finally, we outline the potential clinical utility of dietary interventions, exercise, and bariatric surgery in circumventing the impacts of obesity on cognitive function.

The neural cell adhesion molecule (NCAM) is the predominant carrier of α2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca²⁺transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation ofRas-GRF1(a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.

An association between oxidative stress and muscle atrophy and weakness in vivo is supported by elevated oxidative damage and accelerated loss of muscle mass and force with aging in CuZn-superoxide dismutase-deficient ( Sod1^−/−) mice. The purpose was to determine the basis for low specific force (N/cm²) of gastrocnemius muscles in Sod1^−/− mice and establish the extent to which structural and functional changes in muscles of Sod1^−/− mice resemble those associated with normal aging. We tested the hypothesis that muscle weakness in Sod1^−/− mice is due to functionally denervated fibers by comparing forces during nerve and direct muscle stimulation. No differences were observed for wild-type mice at any age in the forces generated in response to nerve and muscle stimulation. Nerve- and muscle-stimulated forces were also not different for 4-wk-old Sod1^−/− mice, whereas, for 8- and 20-mo-old mice, forces during muscle stimulation were 16 and 30% greater, respectively, than those obtained using nerve stimulation. In addition to functional evidence of denervation with aging, fiber number was not different for Sod1^−/− and wild-type mice at 4 wk, but 50% lower for Sod1^−/− mice by 20 mo, and denervated motor end plates were prevalent in Sod1^−/− mice at both 8 and 20 mo and in WT mice by 28 mo. The data suggest ongoing denervation in muscles of Sod1^−/− mice that results in fiber loss and muscle atrophy. Moreover, the findings support using Sod1^−/− mice to explore mechanistic links between oxidative stress and the progression of deficits in muscle structure and function.

Ischemic stroke and traumatic brain injury (TBI) are among the leading causes of death and disability worldwide with impairments ranging from mild to severe. Many therapies are aimed at improving functional and cognitive recovery by targeting neural repair but have encountered issues involving efficacy and drug delivery. As a result, therapeutic options for patients are sparse. Neurotrophic factors are one of the key mediators of neural plasticity and functional recovery. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) serve as potential therapeutic options to increase neural repair and recovery as they promote neuroprotection and regeneration. BDNF and NGF have demonstrated the ability to improve functional recovery in preclinical and to a lesser extent clinical studies. Direct and indirect methods to increase levels of neurotrophic factors in animal models have been successful in improving postinjury outcome measures. However, the translation of these studies into clinical trials has been limited. Preclinical experiments have largely failed to result in significant impacts in clinical research. This review will focus on the administration of these neurotrophic factors in preclinical and clinical stroke and TBI and the challenges in translating these therapies from the bench to the clinic.