Target For Neurodegenerative Diseases Research Articles

Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases.

Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are representative neurodegenerative diseases (NDs) characterized by degeneration of selective neurons, as well as the lack of effective biomarkers and therapeutic treatments. In the last decade, microRNAs (miRNAs) have gained considerable interest in diagnostics and therapy of NDs, owing to their aberrant expression and their ability to target multiple molecules and pathways. Here, we provide an overview of dysregulated miRNAs in fluids (blood or cerebrospinal fluid) and nervous tissue of AD, PD, and ALS patients. By emphasizing those that are commonly dysregulated in these NDs, we highlight their potential role as biomarkers or therapeutical targets and describe the use of antisense oligonucleotides as miRNA therapies.

Cellular senescence in the aging brain: A promising target for neurodegenerative diseases

Aging is inevitable. Along with reduced ability to maintain the homeostasis of various biological processes, aging gradually deteriorates overall health. Extensive research on the aging brain has identified cellular senescence as a critical risk factor of neurodegeneration and cognitive decline. Associations of cellular senescence with neurodegenerative diseases like Alzheimer’s disease, Down syndrome, Parkinson’s disease, and multiple sclerosis are evident in an extensive body of literature generated over decades of research on aging. Cellular senescence triggers neurodegeneration via a complex interplay of mechanisms including neuroinflammation, mitochondrial dysfunction, oxidative stress burden, deranged protein homeostasis, and compromised nuclear and blood-brain-barrier integrity. Thus, cellular senescence can serve as a primary therapeutic target for various neurodegenerative diseases. This review summarizes the concept of cellular senescence, its role in the aging brain, and how it mediates neurodegeneration in several neurodegenerative disorders. Further, we have also highlighted senolytic therapeutics discovered and employed to ameliorate cellular senescence-associated degenerative diseases. This review can aid in providing directions for repurposing senolytic compounds and finding more therapeutic strategies targeting cellular senescence for the management and treatment of neurodegenerative diseases.

Mitochondria and Other Organelles in Neural Development and Their Potential as Therapeutic Targets in Neurodegenerative Diseases.

The contribution of organelles to neural development has received increasing attention. Studies have shown that organelles such as mitochondria, endoplasmic reticulum (ER), lysosomes, and endosomes play important roles in neurogenesis. Specifically, metabolic switching, reactive oxygen species production, mitochondrial dynamics, mitophagy, mitochondria-mediated apoptosis, and the interaction between mitochondria and the ER all have roles in neurogenesis. Lysosomes and endosomes can regulate neurite growth and extension. Moreover, metabolic reprogramming represents a novel strategy for generating functional neurons. Accordingly, the exploration and application of mechanisms underlying metabolic reprogramming will be beneficial for neural conversion and regenerative medicine. There is adequate evidence implicating the dysfunction of cellular organelles—especially mitochondria—in neurodegenerative disorders, and that improvement of mitochondrial function may reverse the progression of these diseases through the reinforcement of adult neurogenesis. Therefore, these organelles have potential as therapeutic targets for the treatment of neurodegenerative diseases. In this review, we discuss the function of these organelles, especially mitochondria, in neural development, focusing on their potential as therapeutic targets in neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.

Rutin increases alpha-tubulin acetylation via histone deacetylase 6 inhibition.

Microtubules are dynamic cytoskeletal filaments composed of alpha- (α) and beta (β)-tubulin proteins. α-tubulin proteins are posttranslationally acetylated, and loss of acetylation is associated with axonal transport defects, a common alteration contributing to the pathomechanisms of several neurodegenerative diseases. Restoring α-tubulin acetylation by pharmacological inhibition of HDAC6, a primary α-tubulin deacetylase, can rescue impaired transport. Therefore, HDAC6 is considered a promising therapeutic target for neurodegenerative diseases, but currently, there is no clinically approved inhibitor for this purpose. In this study, using drug repurposing strategy, we aimed to identify compounds possessing HDAC6 inhibition activity and inducing α-tubulin acetylation. We systematically analyzed the FDA-approved library by utilizing virtual screening and consensus scoring approaches. Inhibition activities of promising compounds were tested using in vitro assays. Motor neuron-like NSC34 cells were treated with the candidate compounds, and α-tubulin acetylation levels were determined by Western blot. Our results demonstrated that rutin, a natural flavonoid, inhibits cellular HDAC6 activity without inducing any toxicity, and it significantly increases α-tubulin acetylation level in motor neuron-like cells.

Differential expression of MicroRNAs in Alzheimer's disease: a systematic review and meta-analysis.

Alzheimer's disease (AD) results in progressive cognitive decline owing to the accumulation of amyloid plaques and hyperphosphorylated tau. MicroRNAs (miRNAs) have attracted attention as a putative diagnostic and therapeutic target for neurodegenerative diseases. However, existing meta-analyses on AD and its association with miRNAs have produced inconsistent results. The primary objective of this study is to evaluate the magnitude and consistency of differences in miRNA levels between AD patients, mild cognitive impairment (MCI) patients and healthy controls (HC). Articles investigating miRNA levels in blood, brain tissue, or cerebrospinal fluid (CSF) of AD and MCI patients versus HC were systematically searched in PubMed/Medline from inception to February 16th, 2021. Fixed- and random-effects meta-analyses were complemented with the I2 statistic to measure the heterogeneity, assessment of publication bias, sensitivity subgroup analyses (AD severity, brain region, post-mortem versus ante-mortem specimen for CSF and type of analysis used to quantify miRNA) and functional enrichment pathway analysis. Of the 1512 miRNAs included in 61 articles, 425 meta-analyses were performed on 334 miRNAs. Fifty-six miRNAs were significantly upregulated (n = 40) or downregulated (n = 16) in AD versus HC and all five miRNAs were significantly upregulated in MCI versus HC. Functional enrichment analysis confirmed that pathways related to apoptosis, immune response and inflammation were statistically enriched with upregulated pathways in participants with AD relative to HC. This study confirms that miRNAs' expression is altered in AD and MCI compared to HC. These findings open new diagnostic and therapeutic perspectives for this disorder.

Identification of Pharmacophoric Fragments of DYRK1A Inhibitors Using Machine Learning Classification Models.

Dual-specific tyrosine phosphorylation regulated kinase 1 (DYRK1A) has been regarded as a potential therapeutic target of neurodegenerative diseases, and considerable progress has been made in the discovery of DYRK1A inhibitors. Identification of pharmacophoric fragments provides valuable information for structure- and fragment-based design of potent and selective DYRK1A inhibitors. In this study, seven machine learning methods along with five molecular fingerprints were employed to develop qualitative classification models of DYRK1A inhibitors, which were evaluated by cross-validation, test set, and external validation set with four performance indicators of predictive classification accuracy (CA), the area under receiver operating characteristic (AUC), Matthews correlation coefficient (MCC), and balanced accuracy (BA). The PubChem fingerprint-support vector machine model (CA = 0.909, AUC = 0.933, MCC = 0.717, BA = 0.855) and PubChem fingerprint along with the artificial neural model (CA = 0.862, AUC = 0.911, MCC = 0.705, BA = 0.870) were considered as the optimal modes for training set and test set, respectively. A hybrid data balancing method SMOTETL, a combination of synthetic minority over-sampling technique (SMOTE) and Tomek link (TL) algorithms, was applied to explore the impact of balanced learning on the performance of models. Based on the frequency analysis and information gain, pharmacophoric fragments related to DYRK1A inhibition were also identified. All the results will provide theoretical supports and clues for the screening and design of novel DYRK1A inhibitors.

Discovery of Phospholipase D Inhibitors with Improved Drug-like Properties and Central Nervous System Penetrance.

Phospholipase D (PLD) is a phospholipase enzyme responsible for hydrolyzing phosphatidylcholine into the lipid signaling molecule, phosphatidic acid, and choline. From a therapeutic perspective, PLD has been implicated in human cancer progression as well as a target for neurodegenerative diseases, including Alzheimer's. Moreover, knockdown of PLD rescues the ALS phenotype in multiple Drosophila models of ALS (amyotrophic lateral sclerosis) and displays modest motor benefits in an SOD1 ALS mouse model. To further validate whether inhibiting PLD is beneficial for the treatment of ALS, a brain penetrant small molecule inhibitor with suitable PK properties to test in an ALS animal model is needed. Using a combination of ligand-based drug discovery and structure-based design, a dual PLD1/PLD2 inhibitor was discovered that is single digit nanomolar in the Calu-1 cell assay and has suitable PK properties for in vivo studies. To capture the in vivo measurement of PLD inhibition, a transphosphatidylation pharmacodynamic LC-MS assay was developed, in which a dual PLD1/PLD2 inhibitor was found to reduce PLD activity by 15-20-fold.

The mitochondrial protein Sideroflexin 3 (SFXN3) influences neurodegeneration pathways invivo.

Synapses are a primary pathological target in neurodegenerative diseases. Identifying therapeutic targets at the synapse could delay progression of numerous conditions. The mitochondrial protein SFXN3 is a neuronally enriched protein expressed in synaptic terminals and regulated by key synaptic proteins, including α‐synuclein. We first show that SFXN3 uses the carrier import pathway to insert into the inner mitochondrial membrane. Using high‐resolution proteomics on Sfxn3‐KO mice synapses, we then demonstrate that SFXN3 influences proteins and pathways associated with neurodegeneration and cell death (including CSPα and Caspase‐3), as well as neurological conditions (including Parkinson's disease and Alzheimer’s disease). Overexpression of SFXN3 orthologues in Drosophila models of Parkinson's disease significantly reduced dopaminergic neuron loss. In contrast, the loss of SFXN3 was insufficient to trigger neurodegeneration in mice, indicating an anti‐ rather than pro‐neurodegeneration role for SFXN3. Taken together, these results suggest a potential role for SFXN3 in the regulation of neurodegeneration pathways.

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease.

Objective:Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer’s disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer’s disease.Methods:We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer’s disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping.Results:We found that the probable Alzheimer’s disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration.Conclusions:Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Future Advances in Early Phase Clinical Development for Disease Modifying Therapies for Neurodegenerative Diseases

With aging populations in many countries, the prevalence of neurodegenerative diseases is expected to increase in the upcoming decades. Currently, no disease modifying therapies for these conditions exist. Advances in genetics and proteomics have identified novel druggable targets for neurodegenerative diseases. Compounds modulating these targets have recently entered clinical trials. These compounds can be orally administered small drug molecules, intravenously dosed antibodies, intrathecally injected antisense oligonucleotides (ASOs), gene therapies, stem cells or viral vectors. For the development of these compounds to be successful, multiple challenges have to be overcome. In this review we discuss advances in drug development for each of the major neurodegenerative diseases, which, when applied to early phase drug studies, increase the chance of successful clinical development. Here we will limit ourselves to: 1) the use of biomarkers for understanding target and pathway engagement at an early stage of development, 2) novel approaches for increasing blood-brain barrier penetration and 3) advances in understanding cerebrospinal fluid flow dynamics in relation to neurodegeneration and target site distribution for intrathecally administered compounds.

Inflammasome activation in neurodegenerative diseases.

Approximately ten million people are diagnosed with dementia annually since they experience difficulties with memory and thinking skills. Since neurodegenerative diseases are diagnosed late, most of them are difficult to treat. This is due to the increased severity of the disease during the progression when neuroinflammation plays a critical role. The activation of immune cells, especially microglia, plays a crucial role in the development of neurodegenerative diseases. Molecular sensors within these microglia, such as the NLRP3 inflammasome, are activated by signals that represent the hallmarks of neurodegenerative diseases. Here, we first summarize the two activation steps of NLRP3 inflammasome activation. Furthermore, we discuss the key factors that contribute to NLRP3 inflammasome activation in the different neuroinflammatory diseases, like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The prominent NLRP3 inflammasome triggers include amyloid β and tau oligomers in AD, α-synuclein in PD, and superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP43) in ALS. NLRP3 inhibitor treatment has shown promising results in several preclinical mouse models of AD, PD, and ALS. Finally, we postulate that current understandings underpin the potential for NLRP3 inhibitors as a therapeutic target in neurodegenerative diseases.

Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a class of heterogeneous diseases that includes Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Mitochondria play an important role in oxidative balance and metabolic activity of neurons; therefore, mitochondrial dysfunction is associated with NDs and mitochondria are considered a potential treatment target for NDs. Several obstacles, including the blood-brain barrier (BBB) and cell/mitochondrial membranes, reduce the efficiency of drug entry into the target lesions. Therefore, a variety of neuron mitochondrial targeting strategies has been developed. Among them, nanotechnology-based treatments show especially promising results. Owing to their adjustable size, appropriate charge, and lipophilic surface, nanoparticles (NPs) are the ideal theranostic system for crossing the BBB and targeting the neuronal mitochondria. In this review, we discussed the role of dysfunctional mitochondria in ND pathogenesis as well as the physiological barriers to various treatment strategies. We also reviewed the use and advantages of various NPs (including organic, inorganic, and biological membrane-coated NPs) for the treatment and diagnosis of NDs. Finally, we summarized the evidence and possible use for the promising role of NP-based theranostic systems in the treatment of mitochondrial dysfunction-related NDs.

Legumain in the brain of animal models of Alzheimer’s disease (AD) and its promise to be an intervention target for AD

Age is the greatest risk factor for most cases of Alzheimer's disease (AD) as the incidence rises significantly with ageing. Mammalian legumain, a lysosomal asparaginyl endopeptidase recently was suggested as a potential link between aging and AD onset. Herein, we inspected age-related legumain regulation in two animal models of AD and tested its promise to be an intervention target for AD. Male APPswe/PS1dE9 transgenic and the senescence-accelerated mouse prone 8 (SAMP8) mice are the two AD animal models. The age-related expression and activity of legumain in brain tissue of these mice were detected using western blot and enzymatic activity assay. Immunohistochemically staining and Morris water maze test were used to reveal pathological changes in the brain and monitor cognition decline. Mice were administrated with a δ-secretase inhibitor 11 (10 mg/kg, p.o.) once daily for 3 months to suppress brain legumain activity and modify AD-like pathology. The expression level and enzymatic activity of legumain was up-regulated in brains of 5-8-month old SAMP8 and APPswe/PS1dE9 transgenic mice in comparison with age-mated WT mice. Elevation of legumain preceded formation of Aβ plaque and cognitive impairment. Pharmacological inhibition of legumain reduced Aβ production and tau hyperphosphorylation, rescued degeneration of neuronal structural integrity in the cortex and hippocampus of AD mice and attenuated memory loss. In SMAP8 and its control strain SAMR1 mice, the enzymatic activity of brain legumain is almost 20 times lower than that in kidney and liver tissue. Inhibition of brain legumain didn't incur severe side effect. Elevated legumain in a certain brain region can be considered as an abnormal condition and a potential intervention target for neurodegenerative disease, such as AD. But how legumain was up-regulated and activated in the brain of AD model mice remains to be elucidated. Acknowledgements: Mingke Song and this study is supported by the National Natural Science Foundation of China, China (No. 91949116, No.81873807) and Innovative Research Team of High-level Local Universities in Shanghai, China.

TIGAR plays neuroprotective roles in KA-induced excitotoxicity through reducing neuroinflammation and improving mitochondrial function

Excitotoxicity refers to the ability of excessive extracellular excitatory amino acids to damage neurons via receptor activation. It is a crucial pathogenetic process in neurodegenerative diseases. TP53 is confirmed to be involved in excitotoxicity. It is demonstrated that TP53 induced glycolysis and apoptotic regulator (TIGAR)-regulated metabolic pathway can protect against neuronal injury. However, the role of TIGAR in excitotoxicity and specific mechanisms is still unknown. In this study, an in vivo excitotoxicity model was constructed via stereotypical kainic acid (KA) injection into the striatum of mice. KA reduced TIGAR expression levels, neuroinflammatory responses and mitochondrial dysfunction. TIGAR overexpression could reverse KA-induced neuronal injury by reducing neuroinflammation and improving mitochondrial function, thereby exerting neuroprotective effects. Therefore, this study could provide a potential therapeutic target for neurodegenerative diseases.

Endocannabinoid Metabolism and Traumatic Brain Injury.

Traumatic brain injury (TBI) represents a major cause of morbidity and disability and is a risk factor for developing neurodegenerative diseases, including Alzheimer’s disease (AD). However, no effective therapies are currently available for TBI-induced AD-like disease. Endocannabinoids are endogenous lipid mediators involved in a variety of physiological and pathological processes. The compound 2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid with profound anti-inflammatory and neuroprotective properties. This molecule is predominantly metabolized by monoacylglycerol lipase (MAGL), a key enzyme degrading about 85% of 2-AG in the brain. Studies using animal models of inflammation, AD, and TBI provide evidence that inactivation of MAGL, which augments 2-AG signaling and reduces its metabolites, exerts neuroprotective effects, suggesting that MAGL is a promising therapeutic target for neurodegenerative diseases. In this short review, we provide an overview of the inhibition of 2-AG metabolism for the alleviation of neuropathology and the improvement of synaptic and cognitive functions after TBI.

Neurodegenerative Disease: What Potential Therapeutic Role of Acid-Sensing Ion Channels?

Acidic pH shift occurs in many physiological neuronal activities such as synaptic transmission and synaptic plasticity but also represents a characteristic feature of many pathological conditions including inflammation and ischemia. Neuroinflammation is a complex process that occurs in various neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease. Acid-sensing ion channels (ASICs) represent a widely expressed pH sensor in the brain that play a key role in neuroinflammation. On this basis, acid-sensing ion channel blockers are able to exert neuroprotective effects in different neurodegenerative diseases. In this review, we discuss the multifaceted roles of ASICs in brain physiology and pathology and highlight ASIC1a as a potential pharmacological target in neurodegenerative diseases.

The roles of epigenetic modifications in neurodegenerative diseases

In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.

The role of the integral type II transmembrane protein BRI2 in health and disease.

BRI2 is a type II transmembrane protein ubiquitously expressed whose physiological function remains poorly understood. Although several recent important advances have substantially impacted on our understanding of BRI2 biology and function, providing valuable information for further studies on BRI2. These findings have contributed to a better understanding of BRI2 biology and the underlying signaling pathways involved. In turn, these might provide novel insights with respect to neurodegeneration processes inherent to BRI2-related pathologies, namely Familial British and Danish dementias, Alzheimer's disease, ITM2B-related retinal dystrophy, and multiple sclerosis. In this review, we provided astate-of-the-art outline of BRI2 biology, both in physiological and pathological conditions, and discuss the proposed molecular underlying mechanisms. Overall, the BRI2 knowledge here reviewed is of extreme importance and may contribute to propose BRI2 and/or BRI2 proteolytic fragments as novel therapeutic targets for neurodegenerative diseases, such as Alzheimer's disease.

Neurodegenerative Disease: Roles for Sex, Hormones, and Oxidative Stress.

Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50 and 70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex is also an important risk factor. The characteristic of sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions. An understudied sex hormone receptor that can induce activation of oxidative stress signaling is the membrane androgen receptor (mAR). mAR can mediate nicotinamide adenine dinucleotide-phosphate (NADPH) oxidase (NOX)-generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer disease. Further complicating this is that aging can alter sex hormone signaling. Prior to menopause, women experience more estrogens than androgens. During menopause, this sex hormone profile switches in women due to the dramatic ovarian loss of 17β-estradiol with maintained ovarian androgen (testosterone, androstenedione) production. Indeed, aging men have higher estrogens than aging women due to aromatization of androgens to estrogens. Therefore, higher activation of mAR-NOX signaling could occur in menopausal women compared with aged men, mediating the observed sex differences. Understanding of these signaling cascades could provide therapeutic targets for neurodegenerative diseases.

Significance of mitochondrial activity in neurogenesis and neurodegenerative diseases.

Mitochondria play a multidimensional role in the function and the vitality of the neurological system. From the generation of neural stem cells to the maintenance of neurons and their ultimate demise, mitochondria play a critical role in regulating our neural pathways’ homeostasis, a task that is critical to our cognitive health and neurological well-being. Mitochondria provide energy via oxidative phosphorylation for the neurotransmission and generation of an action potential along the neuron’s axon. This paper will first review and examine the molecular subtleties of the mitochondria’s role in neurogenesis and neuron vitality, as well as outlining the impact of defective mitochondria in neural aging. The authors will then summarize neurodegenerative diseases related to either neurogenesis or homeostatic dysfunction. Because of the significant detriment neurodegenerative diseases have on the quality of life, it is essential to understand their etiology and ongoing molecular mechanics. The mitochondrial role in neurogenesis and neuron vitality is essential. Dissecting and understanding this organelle’s role in the genesis and homeostasis of neurons should assist in finding pharmaceutical targets for neurodegenerative diseases.