Cadmium (Cd) is an environmental contaminant, which is a potential risk factor in the progression of aging-associated neurodegenerative diseases. Herein, we have assessed the effects of chronic administration of Cd on cellular oxidative stress and its associated Alzheimer’s disease (AD) pathologies in animal models. Two groups of mice were used, one group administered with saline and the other with Cd (1 mg/kg/day; intraperitoneally) for 3 months. After behavioral studies, molecular/biochemical (Immunoblotting, ELISAs, ROS, LPO, and GSH assays) and morphological analyses were performed. We observed an exacerbation of memory and synaptic deficits in chronic Cd-injected mice. Subacute and chronic Cd escalated reactive oxygen species (ROS), suppressed the master antioxidant enzymes, e.g., nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1, and evoked the stress kinase phospho-c-Jun N-terminal kinase 1 signaling pathways, which may escalate AD pathologies possibly associated with amyloidogenic processes. These findings suggest the regulation of oxidative stress/ROS and its associated amyloid beta pathologies for targeting the Cd-exacerbated AD pathogenesis. In addition, these preclinical animal studies represent a paradigm for epidemiological studies of the human population exposed to chronic and subacute administration of Cd, suggesting avoiding environmental contaminants.

The novel coronavirus (2019-nCoVCOVID-19) belongs to the Beta coronavirus family, which contains MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS-CoV (severe acute respiratory syndrome coronavirus). SARS-CoV-2 activates the innate immune system, thereby activating the inflammatory mechanism, causing the release of inflammatory cytokines. Moreover, it has been suggested that COVID-19 may penetrate the central nervous system, and release inflammatory cytokines in the brains, inducing neuroinflammation and neurodegeneration. Several links connect COVID-19 with Alzheimer’s disease (AD), such as elevated oxidative stress, uncontrolled release of the inflammatory cytokines, and mitochondrial apoptosis. There are severe concerns that excessive immune cell activation in COVID-19 may aggravate the neurodegeneration and amyloid-beta pathology of AD. Here, we have collected the evidence, showing the links between the two diseases. The focus has been made to collect the information on the activation of the inflammation, its contributors, and shared therapeutic targets. Furthermore, we have given future perspectives, research gaps, and overlapping pathological bases of the two diseases. Lastly, we have given the short touch to the drugs that have equally shown rescuing effects against both diseases. Although there is limited information available regarding the exact links between COVID-19 and neuroinflammation, we have insight into the pathological contributors of the diseases. Based on the shared pathological features and therapeutic targets, we hypothesize that the activation of the immune system may induce neurological disorders by triggering oxidative stress and neuroinflammation.

Alzheimer’s disease (AD) is the most predominant age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregates of amyloid beta Aβ1–42 and tau hyperphosphorylation in the brain. It is considered to be the primary cause of cognitive dysfunction. The aggregation of Aβ1–42 leads to neuronal inflammation and apoptosis. Since vitamins are basic dietary nutrients that organisms need for their growth, survival, and other metabolic functions, in this study, the underlying neuroprotective mechanism of nicotinamide (NAM) Vitamin B3 against Aβ1–42 -induced neurotoxicity was investigated in mouse brains. Intracerebroventricular (i.c.v.) Aβ1–42 injection elicited neuronal dysfunctions that led to memory impairment and neurodegeneration in mouse brains. After 24 h after Aβ1–42 injection, the mice were treated with NAM (250 mg/kg intraperitoneally) for 1 week. For biochemical and Western blot studies, the mice were directly sacrificed, while for confocal and “immunohistochemical staining”, mice were perfused transcardially with 4% paraformaldehyde. Our biochemical, immunofluorescence, and immunohistochemical results showed that NAM can ameliorate neuronal inflammation and apoptosis by reducing oxidative stress through lowering malondialdehyde and 2,7-dichlorofluorescein levels in an Aβ1–42-injected mouse brains, where the regulation of p-JNK further regulated inflammatory marker proteins (TNF-α, IL-1β, transcription factor NF-kB) and apoptotic marker proteins (Bax, caspase 3, PARP1). Furthermore, NAM + Aβ treatment for 1 week increased the amount of survival neurons and reduced neuronal cell death in Nissl staining. We also analyzed memory dysfunction via behavioral studies and the analysis showed that NAM could prevent Aβ1–42 -induced memory deficits. Collectively, the results of this study suggest that NAM may be a potential preventive and therapeutic candidate for Aβ1–42 -induced reactive oxygen species (ROS)-mediated neuroinflammation, neurodegeneration, and neurotoxicity in an adult mouse model.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents 60–70% of all dementia cases. AD is characterized by the formation and accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuronal cell loss. Further accumulation of Aβ in the brain induces oxidative stress, neuroinflammation, and synaptic and memory dysfunction. In this study, we investigated the antioxidant and neuroprotective effects of the natural flavonoid lupeol in the Aβ1–42 mouse model of AD. An Intracerebroventricular injection (i.c.v.) of Aβ (3 µL/5 min/mouse) into the brain of a mouse increased the reactive oxygen species (ROS) levels, neuroinflammation, and memory and cognitive dysfunction. The oral administration of lupeol at a dose of 50 mg/kg for two weeks significantly decreased the oxidative stress, neuroinflammation, and memory impairments. Lupeol decreased the oxidative stress via the activation of nuclear factor erythroid 2-related factor-2 (Nrf-2) and heme oxygenase-1 (HO-1) in the brain of adult mice. Moreover, lupeol treatment prevented neuroinflammation by suppressing activated glial cells and inflammatory mediators. Additionally, lupeol treatment significantly decreased the accumulation of Aβ and beta-secretase-1 (BACE-1) expression and enhanced the memory and cognitive function in the Aβ-mouse model of AD. To the best of our knowledge, this is the first study to investigate the anti-oxidative and neuroprotective effects of lupeol against Aβ1–42-induced neurotoxicity. Our findings suggest that lupeol could serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD.

Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb−/−) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb−/−) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb−/− mice were treated with either osmotin (15 μg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb−/− mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb−/− mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb−/− mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb−/− mice.