Aging is characterized by increased oxidative stress, chronic inflammation, and organ dysfunction, which occur in a progressive and irreversible manner. Superoxide dismutase (SOD) serves as a major antioxidant and neutralizes superoxide radicals throughout the body.In vivostudies have demonstrated that copper/zinc superoxide dismutase-deficient (Sod1^−/−) mice show various aging-like pathologies, accompanied by augmentation of oxidative damage in organs. We found that antioxidant treatment significantly attenuated the age-related tissue changes and oxidative damage-associated p53 upregulation inSod1^−/−mice. This review will focus on various age-related pathologies caused by the loss ofSod1and will discuss the molecular mechanisms underlying the pathogenesis inSod1^−/−mice.

Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2^−/−) usingnestin-Cre-loxpsystem. B-Sod2^−/−showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2^−/−, without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice.

Immunotherapy targeting Aβ42 is drawing attention as a possible therapeutic approach for Alzheimer’s disease (AD). Considering the significance of reported oligomerized Aβ42 species, selective targeting of the oligomer will increase the therapeutic efficacy. However, what kinds of oligomers are suitable targets for immunotherapy remains unclear. We previously identified a toxic conformer of Aβ42, which has a turn structure at 22–23 (“toxic turn”), among Aβ42 conformations. This toxic conformer of Aβ42 has been reported to show rapid oligomerization and to exhibit strong neurotoxicity and synaptotoxicity. We recently developed a monoclonal antibody against the toxic conformer (24B3), which demonstrated the increase of the toxic conformer in the cerebrospinal fluid of AD patients, indicating its accumulation in AD patients’ brains. In this study, we evaluated the therapeutic efficacy of 24B3 targeting the toxic conformer in AD model mice. The intraperitoneal administration of 24B3 for 3 months improved cognitive impairment and reduced the toxic conformer levels. Notably, this treatment did not reduce the number of senile plaques. Furthermore, the single intravenous administration of 24B3 suppressed the memory deficit in AD mice. These results suggest that the toxic conformer of Aβ42 with a turn at 22–23 represents one of the promising therapeutic targets.

Although insulin resistance increases the risk of Alzheimer's disease (AD), the mechanisms remain unclear, partly because no animal model exhibits the insulin‐resistant phenotype without persistent hyperglycemia. Here we established an AD model with whole‐body insulin resistance without persistent hyperglycemia (APP/IR‐dKI mice) by crossbreeding constitutive knock‐in mice with P1195L‐mutated insulin receptor (IR‐KI mice) and those with mutated amyloid precursor protein (App^NL‐G‐F mice: APP‐KI mice). APP/IR‐dKI mice exhibited cognitive impairment at an earlier age than APP‐KI mice. Since cholinergic dysfunction is a major characteristic of AD, pharmacological interventions on the cholinergic system were performed to investigate the mechanism. Antagonism to a nicotinic acetylcholine receptor α7 (nAChRα7) suppressed cognitive function and cortical blood flow (CBF) response to cholinergic‐regulated peripheral stimulation in APP‐KI mice but not APP/IR‐dKI mice. Cortical expression of Chrna7, encoding nAChRα7, was downregulated in APP/IR‐dKI mice compared with APP‐KI. Amyloid β burden did not differ between APP‐KI and APP/IR‐dKI mice. Therefore, insulin resistance, not persistent hyperglycemia, induces the earlier onset of cognitive dysfunction and CBF deregulation mediated by nAChRα7 downregulation. Our mouse model will help clarify the association between type 2 diabetes mellitus and AD.

The oxidative damages induced by a redox imbalance cause age-related changes in cells and tissues. Superoxide dismutase (SOD) enzymes play a pivotal role in the antioxidant system and they also catalyze superoxide radicals. Since the loss of cytoplasmic SOD (SOD1) resulted in aging-like phenotypes in several types of murine tissue, SOD1 is essential for the maintenance of tissue homeostasis. Melinjo (Gnetum gnemonLinn) seed extract (MSE) contains trans-resveratrol (RSV) and resveratrol derivatives, including gnetin C, gnemonoside A, and gnemonoside D. MSE intake also exerts no adverse events in human study. In the present studies, we investigated protective effects of MSE on age-related skin pathologies in mice. Orally MSE and RSV treatment reversed the skin thinning associated with increased oxidative damage in theSod1^−/−mice. Furthermore, MSE and RSV normalized gene expression ofCol1a1andp53and upregulated gene expression ofSirt1in skin tissues.In vitroexperiments revealed that RSV significantly promoted the viability ofSod1^−/−fibroblasts. These finding demonstrated that RSV in MSE stably suppressed an intrinsic superoxide generationin vivoandin vitroleading to protecting skin damages. RSV derivative-rich MSE may be a powerful food of treatment for age-related skin diseases caused by oxidative damages.

Piccolo, a presynaptic cytomatrix protein, plays a role in synaptic vesicle trafficking in the presynaptic active zone. Certain single-nucleotide polymorphisms of the Piccolo-encoding gene PCLO are reported to be associated with mental disorders. However, a few studies have evaluated the relationship between Piccolo dysfunction and psychotic symptoms. Therefore, we investigated the neurophysiological and behavioral phenotypes in mice with Piccolo suppression in the medial prefrontal cortex (mPFC). Downregulation of Piccolo in the mPFC reduced regional synaptic proteins, accompanied with electrophysiological impairments. The Piccolo-suppressed mice showed an enhanced locomotor activity, impaired auditory prepulse inhibition, and cognitive dysfunction. These abnormal behaviors were partially ameliorated by the antipsychotic drug risperidone. Piccolo-suppressed mice received mild social defeat stress showed additional behavioral despair. Furthermore, the responses of these mice to extracellular glutamate and dopamine levels induced by the optical activation of mPFC projection in the dorsal striatum (dSTR) were inhibited. Similarly, the Piccolo-suppressed mice showed decreased depolarization-evoked glutamate and -aminobutyric acid elevations and increased depolarization-evoked dopamine elevation in the dSTR. These suggest that Piccolo regulates neurotransmission at the synaptic terminal of the projection site. Reduced neuronal connectivity in the mPFC-dSTR pathway via suppression of Piccolo in the mPFC may induce behavioral impairments observed in schizophrenia.