Amyloid Beta and MicroRNAs in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive mental illness characterized by memory loss and multiple cognitive impairments. In the last several decades, significant progress has been made in understanding basic biology, molecular mechanisms, and development of biomarkers and therapeutic drugs. Multiple cellular changes are implicated in the disease process including amyloid beta and phosphorylation of tau synaptic damage and mitochondrial dysfunction in AD. Among these, amyloid beta is considered a major player in the disease process. Recent advancements in molecular biology revealed that microRNAs (miRNAs) are considered potential biomarkers in AD with a focus on amyloid beta. In this article we discussed several aspects of AD including its prevalence, classifications, risk factors, and amyloid species and their accumulation in subcellular compartments. This article also discusses the discovery and biogenesis of miRNAs and their relevance to AD. Today’s research continues to add to the wealth of miRNA data that has been accumulated, however, there still lacks clear-cut understanding of the physiological relevance of miRNAs to AD. MiRNAs appear to regulate translation of gene products in AD and other human diseases. However, the mechanism of how many of these miRNAs regulate both the 5′ and 3′UTR of amyloid precursor protein (APP) processing is still being extrapolated. Hence, we still need more research on miRNAs and APP/amyloid beta formation in the progression and pathogenesis of AD

Mitochondrial Oxidative Damage in Aging and Alzheimer's Disease: Implications for Mitochondrially Targeted Antioxidant Therapeutics

The overall aim of this article is to review current therapeutic strategies for treating AD, with a focus on mitochondrially targeted antioxidant treatments. Recent advances in molecular, cellular, and animal model studies of AD have revealed that amyloid precursor protein derivatives, including amyloid beta (Aβ) monomers and oligomers, are likely key factors in tau hyperphosphorylation, mitochondrial oxidative damage, inflammatory changes, and synaptic failure in the brain tissue of AD patients. Several therapeutic strategies have been developed to treat AD, including anti-inflammatory, antioxidant, and antiamyloid approaches. Among these, mitochondrial antioxidant therapy has been found to be the most efficacious in reducing pathological changes and in not producing adverse effects; thus, mitochondrial antioxidant therapy is promising as a treatment for AD patients. However, a major limitation in applying mitochondrial antioxidants to AD treatment has been the inability of researchers to enhance antioxidant levels in mitochondria. Recently, however, there has been a breakthrough. Researchers have recently been able to promote the entry of certain antioxidants—including MitoQ, MitoVitE, MitoPBN, MitoPeroxidase, and amino acid and peptide-based SS tetrapeptides—into mitochondria, several hundred-fold more than do natural antioxidants. Once in the mitochondria, they rapidly neutralize free radicals and decrease mitochondrial toxicity. Thus, mitochondrially targeted antioxidants are promising candidates for treating AD patients

COVID-19 and Rheumatoid Arthritis Crosstalk: Emerging Association, Therapeutic Options and Challenges

Hyperactivation of immune responses resulting in excessive release of pro-inflammatory mediators in alveoli/lung structures is the principal pathological feature of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cytokine hyperactivation in COVID-19 appears to be similar to those seen in rheumatoid arthritis (RA), an autoimmune disease. Emerging evidence conferred the severity and risk of COVID-19 to RA patients. Amid the evidence of musculoskeletal manifestations involving immune-inflammation-dependent mechanisms and cases of arthralgia and/or myalgia in COVID-19, crosstalk between COVID-19 and RA is often debated. The present article sheds light on the pathological crosstalk between COVID-19 and RA, the risk of RA patients in acquiring SARS-CoV-2 infection, and the aspects of SARS-CoV-2 infection in RA development. We also conferred whether RA can exacerbate COVID-19 outcomes based on available clinical readouts. The mechanistic overlapping in immune-inflammatory features in both COVID-19 and RA was discussed. We showed the emerging links of angiotensin-converting enzyme (ACE)-dependent and macrophage-mediated pathways in both diseases. Moreover, a detailed review of immediate challenges and key recommendations for anti-rheumatic drugs in the COVID-19 setting was presented for better clinical monitoring and management of RA patients. Taken together, the present article summarizes available knowledge on the emerging COVID-19 and RA crosstalk and their mechanistic overlaps, challenges, and therapeutic options

Toxicity of Neurons Treated with Herbicides and Neuroprotection by Mitochondria-Targeted Antioxidant SS31

The purpose of this study was to determine the neurotoxicity of two commonly used herbicides: picloram and triclopyr and the neuroprotective effects of the mitochondria-targeted antioxidant, SS31. Using mouse neuroblastoma (N2a) cells and primary neurons from C57BL/6 mice, we investigated the toxicity of these herbicides, and protective effects of SS1 peptide against picloram and triclopyr toxicity. We measured total RNA content, cell viability and mRNA expression of peroxiredoxins, neuroprotective genes, mitochondrial-encoded electron transport chain (ETC) genes in N2a cells treated with herbicides and SS31. Using primary neurons from C57BL/6 mice, neuronal survival was studied in neurons treated with herbicides, in neurons pretreated with SS31 plus treated with herbicides, neurons treated with SS31 alone, and untreated neurons. Significantly decreased total RNA content, and cell viability in N2a cells treated with picloram and triclopyr were found compared to untreated N2a cells. Decreased mRNA expression of neuroprotective genes, and ETC genes in cells treated with herbicides was found compared to untreated cells. Decreased mRNA expression of peroxiredoxins 1–6 in N2a cells treated with picloram was found, suggesting that picloram affects the antioxidant enzymes in N2a cells. Immunofluorescence analysis of primary neurons revealed that decreased neuronal branching and degenerating neurons in neurons treated with picloram and triclopyr. However, neurons pretreated with SS31 prevented degenerative process caused by herbicides. Based on these results, we propose that herbicides—picloram and triclopyr appear to damage neurons, and the SS31 peptide appears to protect neurons from herbicide toxicity

White Matter Deterioration May Foreshadow Impairment of Emotional Valence Determination in Early-Stage Dementia of the Alzheimer Type

In Alzheimer Disease (AD), non-verbal skills often remain intact for far longer than verbally mediated processes. Four (1 female, 3 males) participants with early-stage Clinically Diagnosed Dementia of the Alzheimer Type (CDDAT) and eight neurotypicals (NTs; 4 females, 4 males) completed the emotional valence determination test (EVDT) while undergoing BOLD functional magnetic resonance imaging (fMRI). We expected CDDAT participants to perform just as well as NTs on the EVDT, and to display increased activity within the bilateral amygdala and right anterior cingulate cortex (r-ACC). We hypothesized that such activity would reflect an increased reliance on these structures to compensate for on-going neuronal loss in frontoparietal regions due to the disease. We used diffusion tensor imaging (DTI) to determine if white matter (WM) damage had occurred in frontoparietal regions as well. CDDAT participants had similar behavioral performance and no differences were observed in brain activity or connectivity patterns within the amygdalae or r-ACC. Decreased fractional anisotropy (FA) values were noted, however, for the bilateral superior longitudinal fasciculi and posterior cingulate cortex (PCC). We interpret these findings to suggest that emotional valence determination and non-verbal skill sets are largely intact at this stage of the disease, but signs foreshadowing future decline were revealed by possible WM deterioration. Understanding how non-verbal skill sets are altered, while remaining largely intact, offers new insights into how non-verbal communication may be more successfully implemented in the care of AD patients and highlights the potential role of DTI as a presymptomatic biomarker

Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington\u27s disease

Neurons in Huntington\u27s disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington\u27s disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry

Anti-epileptic effect of Ganoderma lucidum polysaccharides by inhibition of intracellular calcium accumulation and stimulation of expression of CaMKII a in epileptic hippocampal neurons

Purpose: To investigate the mechanism of the anti-epileptic effect of Ganoderma lucidum polysaccharides (GLP), the changes of intracellular calcium and CaMK II a expression in a model of epileptic neurons were investigated. Method: Primary hippocampal neurons were divided into: 1) Control group, neurons were cultured with Neurobasal medium, for 3 hours; 2) Model group I: neurons were incubated with Mg2+ free medium for 3 hours; 3) Model group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with the normal medium for a further 3 hours; 4) GLP group I: neurons were incubated with Mg2+ free medium containing GLP (0.375 mg/ml) for 3 hours; 5) GLP group II: neurons were incubated with Mg2+ free medium for 3 hours then cultured with a normal culture medium containing GLP for a further 3 hours. The CaMK II a protein expression was assessed by Western-blot. Ca2+ turnover in neurons was assessed using Fluo-3/AM which was added into the replacement medium and Ca2+ turnover was observed under a laser scanning confocal microscope. Results: The CaMK II a expression in the model groups was less than in the control groups, however, in the GLP groups, it was higher than that observed in the model group. Ca2+ fluorescence intensity in GLP group I was significantly lower than that in model group I after 30 seconds, while in GLP group II, it was reduced significantly compared to model group II after 5 minutes. Conclusion: GLP may inhibit calcium overload and promote CaMK II a expression to protect epileptic neuron

Metabotyping of docosahexaenoic acid - Treated alzheimer's disease cell model

10.1371/journal.pone.0090123PLoS ONE92-POLN

CART Peptide Is a Potential Endogenous Antioxidant and Preferentially Localized in Mitochondria

The multifunctional neuropeptide Cocaine and Amphetamine Regulated Transcript (CART) is secreted from hypothalamus, pituitary, adrenal gland and pancreas. It also can be found in circulatory system. This feature suggests a general role for CART in different cells. In the present study, we demonstrate that CART protects mitochondrial DNA (mtDNA), cellular proteins and lipids against the oxidative action of hydrogen peroxide, a widely used oxidant. Using cis-parinaric acid as a sensitive reporting probe for peroxidation in membranes, and a lipid-soluble azo initiator of peroxyl radicals, 2,2′-Azobis(2,4-dimethylvaleronitrile) we found that CART is an antioxidant. Furthermore, we found that CART localized to mitochondria in cultured cells and mouse brain neuronal cells. More importantly, pretreatment with CART by systemic injection protects against a mouse oxidative stress model, which mimics the main features of Parkinson's disease. Given the unique molecular structure and biological features of CART, we conclude that CART is an antioxidant peptide (or antioxidant hormone). We further propose that it may have strong therapeutic properties for human diseases in which oxidative stress is strongly involved such as Parkinson's disease

Association between Changes in Muscle Quality with Exercise Training and Changes in Cardiorespiratory Fitness Measures in Individuals with Type 2 Diabetes Mellitus: Results from the HART-D Study

Introduction: Type 2 diabetes mellitus (T2DM) is associated with a reduction in muscle quality. However, there is inadequate empirical evidence to determine whether changes in muscle quality following exercise are associated with improvement in cardiorespiratory fitness (CRF) in individuals with T2DM. The objective of this study was to investigate the association between change in muscle quality following a 9-month intervention of aerobic training (AT), resistance training (RT) or a combination of both (ATRT) and cardiorespiratory fitness (CRF) in individuals with T2DM. Material and Methods A total of 196 participants were randomly assigned to a control, AT, RT, or combined ATRT for a 9-months intervention. The exposure variable was change in muscle quality [(Post: leg muscle strength/leg muscle mass)-[(Pre: leg muscle strength/leg muscle mass)]. Dependent variables were change in CRF measures including absolute and relative VO2peak, and treadmill time to exhaustion (TTE) and estimated metabolic equivalent task (METs). Results Continuous change in muscle quality was independently associated with change in absolute (β = 0.015; p = 0.019) and relative (β = 0.200; p = 0.005) VO2peak, and TTE (β = 0.170; p = 0.043), but not with estimated METs (p > 0.05). A significant trend was observed across tertiles of change in muscle quality for changes in absolute (β = 0.050; p = 0.005) and relative (β = 0.624; p = 0.002) VO2peak following 9 months of exercise training. No such association was observed for change in TTE and estimated METs (p > 0.05). Discussion: The results from this ancillary study suggest that change in muscle quality following exercise training is associated with a greater improvement in CRF in individuals with T2DM. Given the effect RT has on increasing muscle quality, especially as part of a recommended training program (ATRT), individuals with T2DM should incorporate RT into their AT regimens to optimize CRF improvement