Beta amyloid (Aβ) is well accepted to play a central role in the pathogenesis of Alzheimer’s disease (AD). The present work evaluated the therapeutic effects of low-level laser irradiation (LLI) on Aβ-induced neurotoxicity in rat hippocampus. Aβ 1–42 was injected bilaterally to the hippocampus CA1 region of adult male rats, and 2-minute daily LLI treatment was applied transcranially after Aβ injection for 5 consecutive days. LLI treatment suppressed Aβ-induced hippocampal neurodegeneration and long-term spatial and recognition memory impairments. Molecular studies revealed that LLI treatment: (1) restored mitochondrial dynamics, by altering fission and fusion protein levels thereby suppressing Aβ-induced extensive fragmentation; (2) suppressed Aβ-induced collapse of mitochondrial membrane potential; (3) reduced oxidized mitochondrial DNA and excessive mitophagy; (4) facilitated mitochondrial homeostasis via modulation of the Bcl-2-associated X protein/B-cell lymphoma 2 ratio and of mitochondrial anti-oxidant expression; (5) promoted cytochrome c oxidase activity and adenosine triphosphate synthesis; (6) suppressed Aβ-induced glucose-6-phosphate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activity; (7) enhanced the total antioxidant capacity of hippocampal CA1 neurons, whereas reduced the oxidative damage; and (8) suppressed Aβ-induced reactive gliosis, inflammation, and tau hyperphosphorylation. Although development of AD treatments has focused on reducing cerebral Aβ levels, by the time the clinical diagnosis of AD or mild cognitive impairment is made, the brain is likely to have already been exposed to years of elevated Aβ levels with dire consequences for multiple cellular pathways. By alleviating a broad spectrum of Aβ-induced pathology that includes mitochondrial dysfunction, oxidative stress, neuroinflammation, neuronal apoptosis, and tau pathology, LLI could represent a new promising therapeutic strategy for AD.

17β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we used a forebrain-neuron-specific aromatase knock-out (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70–80% decrease in aromatase and forebrain E2 levels compared with FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory, and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenous in vivo E2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore, in vitro studies using FBN-ARO-KO hippocampal slices revealed that, whereas induction of long-term potentiation (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect could be fully rescued by acute E2 treatment in vitro . Mechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. In addition, acute E2 rescue of LTP in hippocampal FBN-ARO-KO slices could be blocked by administration of a MEK/ERK inhibitor, further suggesting a key role for rapid ERK signaling in neuronal E2 effects. In conclusion, the findings provide evidence of a critical role for neuron-derived E2 in regulating synaptic plasticity and cognitive function in the male and female brain. SIGNIFICANCE STATEMENT The steroid hormone 17β-estradiol (E2) is well known to be produced in the ovaries in females. Intriguingly, forebrain neurons also express aromatase, the E2 biosynthetic enzyme, but the precise functions of neuron-derived E2 is unclear. Using a novel forebrain-neuron-specific aromatase knock-out mouse model to deplete neuron-derived E2, the current study provides direct genetic evidence of a critical role for neuron-derived E2 in the regulation of rapid AKT-ERK and CREB-BDNF signaling in the mouse forebrain and demonstrates that neuron-derived E2 is essential for normal expression of LTP, synaptic plasticity, and cognitive function in both the male and female brain. These findings suggest that neuron-derived E2 functions as a novel neuromodulator in the forebrain to control synaptic plasticity and cognitive function.

Recent work has suggested that exercise may be beneficial in preventing or ameliorating symptoms of several neurological disorders, although the mechanism is not entirely understood. The current study was designed to examine the potential beneficial effect of treadmill exercise upon cognitive function in a streptozotocin (STZ)-induced rat model of Alzheimer’s disease (AD). Animals underwent treadmill exercise (30 min/day, 5 days/week) for 4 weeks after bilateral STZ intracerebroventricular injection (2.4 mg/kg). We demonstrated that treadmill exercise significantly attenuated STZ-induced neurodegeneration in the rat hippocampal CA1 region and strongly preserved hippocampal-dependent cognitive functioning. Further mechanistic investigation displayed a marked suppression of STZ-induced amyloid-β accumulation and tau phosphorylation. Intriguingly, treadmill exercise remarkably inhibited reactive gliosis following STZ insult and effectively shifted activated microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, which was correlated with a significantly reduced expression of pro-inflammatory mediators and a corresponding enhancement of anti-inflammatory cytokine expression in the hippocampus. Furthermore, treadmill exercise caused a robust suppression of oxidative damage as evidenced by significantly reduced peroxynitrite production, lipid peroxidation, and oxidized DNA damage. Finally, treadmill exercise strongly attenuated STZ-induced mitochondrial dysfunction manifested by a dramatically elevated intra-mitochondrial cytochrome c oxidase activity and ATP synthesis, and markedly inhibited neuronal apoptosis in the hippocampus. These findings demonstrate that treadmill exercise has a multifactorial effect to attenuate many of the pathological processes that play a key role in AD, and provide further support for the beneficial role of exercise as a potential therapeutic option in AD treatment.

Rationale: Previous studies indicate uncoupling protein-2 (UCP2) as an antioxidant defense against endothelial dysfunction in hypertension. UCP2 also regulates insulin secretion and action. However, the role of UCP2 in endothelial dysfunction associated with diabetes and obesity is unclear.Objective: UCP2 protects against endothelial dysfunction induced by high-fat diet through inhibition of reactive oxygen species (ROS) production, and subsequent increase of nitric oxide bioavailability. Methods and Results:Endothelium-dependent relaxation (EDR) in aortae and mesenteric arteries in response to acetylcholine was measured in wire myograph. Flow-mediated vasodilatation in 2 nd -order mesenteric arteries was measured in pressure myograph. ROS production is measured by CM-H 2 DCFDA and DHE fluorescence. High-glucose exposure reduced EDR in mouse aortae, which was exaggerated in UCP2 knockout (KO) mice, whereas UCP2 overexpression by adenoviral infection (AdUCP2) restored the impaired EDR. Impairment of EDR and flow-mediated vasodilatation in aortae and mesenteric arteries from high-fat diet-induced obese mice (DIO) was exaggerated in UCP2KO DIO mice compared with wild-type DIO littermates, whereas AdUCP2 i.v. injection restored both EDR and flow-mediated vasodilatation in DIO mice. Improved EDR in mesenteric arteries was inhibited by nitric oxide synthase inhibitor. UCP2 overexpression also inhibited intracellular ROS production in the en face endothelium of aorta and mesenteric artery of DIO mice, whereas UCP2 deficiency enhanced ROS production. Key Words: uncoupling protein Ⅲ oxidative stress Ⅲ endothelial dysfunction Ⅲ vasodilatation Ⅲ diabetes T he underlying mechanisms by which diabetes increases the risk of cardiovascular disease are incompletely understood, but it can be triggered by endothelial cell dysfunction that initiates the development of atherosclerosis. Clinical studies show that high-fat diet impairs endothelial function in humans. 1,2 Recent evidence indicates that reactive oxygen species (ROS) produced in mitochondria contributes to the pathogenesis of cardiovascular diseases. [3][4][5] Mitochondrial ROS is also related to diabetes and its complications. 6 In endothelial cells, hyperglycemia induces mitochondrial ROS generation. 7,8 Targeting ROS by antioxidants such as tempol or mitochondrial targeted antioxidants improve endothelium-dependent vasodilatation in hypertensive and diabetic mouse and rat. 9 -13 The uncoupling protein-2 (UCP2) is an anion transporter in the inner membrane, which reduces the electrochemical gradient and thus attenuates mitochondrial ROS production. 14 UCP2 regulates insulin secretion and insulin sensitivity. 15,16 In endothelial cells, UCP2 overexpression inhibits apoptosis while enhancing angiogenesis through amelioration of mitochondrial ROS. 17-20 UCP2 deficiency increases vascular dysfunction and organ damage in ischemic stroke, atherosclerosis, and hypertension. [21][22][23] These studies indicate that UCP2 is protective against vascular diseases through lower...

Recent work has indicated that photobiomodulation (PBM) may beneficially alter the pathological status of several neurological disorders, although the mechanism currently remains unclear. The current study was designed to investigate the beneficial effect of PBM on behavioral deficits and neurogenesis in a photothrombotic (PT) model of ischemic stroke in rats. From day 1 to day 7 after the establishment of PT model, 2-minute daily PBM (CW, 808nm, 350mW/cm, total 294J at scalp level) was applied on the infarct injury area (1.8mm anterior to the bregma and 2.5mm lateral from the midline). Rats received intraperitoneal injections of 5-bromodeoxyuridine (BrdU) twice daily (50mg/kg) from day 2 to 8 post-stoke, and samples were collected at day 14. We demonstrated that PBM significantly attenuated behavioral deficits and infarct volume induced by PT stroke. Further investigation displayed that PBM remarkably enhanced neurogenesis and synaptogenesis, as evidenced by immunostaining of BrdU, Ki67, DCX, MAP2, spinophilin, and synaptophysin. Mechanistic studies suggested beneficial effects of PBM were accompanied by robust suppression of reactive gliosis and the production of pro-inflammatory cytokines. On the contrary, the release of anti-inflammatory cytokines, cytochrome c oxidase activity and ATP production in peri-infarct regions were elevated following PBM treatment. Intriguingly, PBM could effectively switch an M1 microglial phenotype to an anti-inflammatory M2 phenotype. Our novel findings indicated that PBM is capable of promoting neurogenesis after ischemic stroke. The underlying mechanisms may rely on: 1) promotion of proliferation and differentiation of internal neuroprogenitor cells in the peri-infarct zone; 2) improvement of the neuronal microenvironment by altering inflammatory status and promoting mitochondrial function. These findings provide strong support for the promising therapeutic effect of PBM on neuronal repair following ischemic stroke.