Alkaloid's undiscovered neuroprotective potential: a multi-target strategy to fight against neurodegenerative illnesses.

This Special Issue comprises nine reviews offering perspectives from the development of neurodegeneration in different pathologies to neuronal protection, providing new views on the mechanism of neurodegeneration and associated processes and a summary of the progress in neuroscience. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions to The FEBS Journal.

Activation of Nrf2 signaling as a common treatment of neurodegenerative diseases.

Traditionally, apathy has been viewed as a symptom indicating loss of interest or emotions. This paper evaluates evidence that neuropsychiatric disorders also produce a syndrome of apathy. Both the symptom and the syndrome of apathy are of conceptual interest because they signify loss of motivation. An apathy syndrome is defined as a syndrome of primary motivational loss, that is, loss of motivation not attributable to emotional distress, intellectual impairment, or diminished level of consciousness. Loss of motivation due to disturbance of intellect, emotion, or level of consciousness defines the symptom of apathy. Neuropsychiatric literature dealing with apathy is reviewed within the framework of three approaches to defining the concept of a syndrome. Clinical and investigative approaches for evaluating apathy when it occurs in association with other syndromes are described.

Immune gene network of neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD)

The monovalent cation lithium, whose introduction in psychiatry dates back at the end of the 1940s, remains the first-line agent in the management of patients with bipolar disorder (BD). It is effective in the treatment of moderate-to-severe acute mania, prophylactic for recurrent manic and depressive episodes, and reduces the risk of suicide. It can also boost antidepressants effects in the treatment of major depressive disorder (Albert et al., 2014). More recently, a growing body of evidence seems to suggest that the benefits of lithium extend beyond mood stabilization. In vitro, lithium has been shown to provide neuroprotection against excitotoxicity induced by glutamate and N-methyl-D-aspartate (NMDA) receptor activation, calcium, thapsigargin, β-amyloid, aging, serum/growth factor deprivation, low potassium concentration, C2-ceramide, aluminum, ouabain, and specific HIV regulatory proteins. Lithium's neuroprotective effects have further been demonstrated in a series of in vivo animal models of ischemic/hemorrhagic stroke, traumatic brain/spinal cord injury (TBI/SCI), Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), Parkinson's disease (PD), retinal degeneration, multiple sclerosis (MS), alcohol-induced degeneration, Down syndrome, spinocerebellar ataxia-1, HIV-associated neurotoxicity, and irradiation (Chiu et al., 2013). In spite of this, very little is understood about its mechanism of action. Recent research findings indicate that lithium's neuroprotective effects may stem, at least in part, from its ability to inhibit the glycogen synthase kinase-3β (GSK-3β) by directly binding to its enzyme's magnesium-sensitive site and indirectly by enhancing phosphorylation of this kinase at specific serine residues. Indeed lithium's direct inhibition of GSK-3β leads to activation of several transcription factors, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), heat-shock factor-1 (HSF-1), and β-catenin, with subsequent induction of major neurotrophic, angiogenic, anti-inflammatory, and anti-apoptotic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), heat shock protein 70 (HSP70), and B-cell lymphoma/leukemia-2 protein (Bcl-2), respectively. Suppressed GSK-3β further reduces the activity of the pro-apoptotic proteins p53 and Bax and their negative regulatory action on Bcl-2. Noteworthy, BDNF and NGF have been reported to function as both downstream molecules resulting from the inhibition of GSK-3β and upstream signals able to inhibit this molecular pathway via specific survival signaling cascades such as the phosphatidylinositol-3-kinase (PI3K)/Akt and the MAP kinase (MEK)/ERK pathways. Lithium also indirectly inhibits GSK-3β via PI3K-dependent activation of protein kinase C (PKC), cAMP-dependent activation of protein kinase A (PKA), and the Wnt/β-catenin pathway (via Frizzled receptors). On the other hand, by decreasing inositol 1,4,5-trisphosphate (IP3) levels, lithium has been shown to induce autophagy, a sort of ‘quality control’ process believed to be particularly important in neurodegenerative disorders such as HD, AD, ALS, and PD characterized by the accumulation of misfolded disease-causing proteins. In these same neurodegenerative disorders as well as in stroke, TBI/SCI, retinal degeneration, MS, and HIV, lithium inhibits glutamate-induced excitotoxicity mediated by NMDA receptors, specifically attenuating the NR2B subunit constitutive tyrosine phosphorylation, and subsequent calcium influx, thus suppressing excitotoxicity-induced p38 and c-Jun N-terminal kinase (JNK), and subsequent transcription factor activator protein-1 (AP-1) activation to block neuronal apoptosis. Inhibition of oxidative stress, implicated in numerous central nervous system (CNS) disorders such as BD, stroke, TBI/SCI, HD, AD, and ALS may further underlie lithium beneficial effects towards these pathologies (Chiu et al., 2013, Figure 1).

Mitochondria: The Next (Neurode)Generation

Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD). We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD. In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them. In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction. We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.

BackgroundNeurodegenerative diseases (NDs), including Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Parkinson's disease (PD) are characterized by the accumulation of misfolded proteins and progressive loss of neurons. However, whether a neurodegeneration transcriptomic signature exists remains uncertain. Thus, we aimed to explore differentially expressed genes (DEGs) in common to AD, HD, MS, and PD. We also seek to evaluate the effect of single nucleotide polymorphisms (SNPs) derived from the NDs‐shared DEGs on AD pathophysiology.MethodsWe obtained RNA‐sequencing and microarray datasets of vulnerable brain regions of AD, HD, MS, and PD individuals from the Gene Expression Omnibus. Differential gene expression analysis (adjusted p‐value < 0.05) was conducted to identify DEGs in common among these four NDs. Then, we examined the impact of shared DEG‐related SNPs on amyloid and tau burden in AD through a linear regression model adjusted for the covariates of age, sex, and ApoEe4 status. We obtained DEG‐related SNPs and amyloid‐ and tau‐PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).ResultsWe identified 467 DEGs in common among AD, HD, MS, and PD vulnerable brain regions (Figure 1, p‐value < 0.05). From these DEGs, 15,574 SNPs were available in ADNI. Linear regression analysis revealed that IQGAP2 rs79679327 carriers had higher tau accumulation independently of amyloid burden (Figure 2, p‐value = 0.001; carriers: n = 21, mean age ± standard deviation (SD) = 72.76 ± 4.54; non‐carriers: n = 176, mean age ± SD = 71.64 ± 6.85).ConclusionHere, we show transcriptional similarities across four NDs. In AD, individuals carrying the IQGAP2 rs79679327 variant exhibited greater tau accumulation, regardless of amyloid. Our findings may provide insights into neurodegenerative traits, through a common signature of neurodegeneration.

BackgroundNeurodegenerative diseases (NDs), including Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Parkinson's disease (PD) are characterized by the accumulation of misfolded proteins and progressive loss of neurons. However, whether a neurodegeneration transcriptomic signature exists remains uncertain. Thus, we aimed to explore differentially expressed genes (DEGs) in common to AD, HD, MS, and PD. We also seek to evaluate the effect of single nucleotide polymorphisms (SNPs) derived from the NDs‐shared DEGs on AD pathophysiology.MethodsWe obtained RNA‐sequencing and microarray datasets of vulnerable brain regions of AD, HD, MS, and PD individuals from the Gene Expression Omnibus. Differential gene expression analysis (adjusted p‐value < 0.05) was conducted to identify DEGs in common among these four NDs. Then, we examined the impact of shared DEG‐related SNPs on amyloid and tau burden in AD through a linear regression model adjusted for the covariates of age, sex, and ApoEε4 status. We obtained DEG‐related SNPs and amyloid‐ and tau‐PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).ResultsWe identified 467 DEGs in common among AD, HD, MS, and PD vulnerable brain regions (Figure 1, p‐value < 0.05). From these DEGs, 15,574 SNPs were available in ADNI. Linear regression analysis revealed that IQGAP2 rs79679327 carriers had higher tau accumulation independently of amyloid burden (Figure 2, p‐value = 0.001; carriers: n = 21, mean age ± standard deviation (SD) = 72.76 ± 4.54; non‐carriers: n = 176, mean age ± SD = 71.64 ± 6.85).ConclusionHere, we show transcriptional similarities across four NDs. In AD, individuals carrying the IQGAP2 rs79679327 variant exhibited greater tau accumulation, regardless of amyloid. Our findings may provide insights into neurodegenerative traits, through a common signature of neurodegeneration.

Nilotinib: from animal-based studies to clinical investigation in Alzheimer's disease patients.

Neurodegeneration is the progressive loss of neurons that results in neurodegenerative diseases (NDs). Currently, there are few effective treatments for NDs, such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Huntington's disease, which involve gradual neuronal death and cognitive deterioration. Alkaloids are naturally occurring molecules with a variety of biological properties. Recent studies have shown that these compounds may be able to modulate signaling pathways linked to many diseases. Alkaloids, with their antioxidant and neuroprotective properties, have the potential to treat neurodegeneration by simultaneously affecting multiple disease parts and modifying neuroinflammatory responses. These interact with various molecular targets, such as transcription factors, receptors, and enzymes involved in neuronal survival and homeostasis. The development of complete therapeutic techniques can be facilitated by alkaloid-based multi-target approaches, which challenge the intricate nature of neurodegenerative pathways. The review highlights the potential of alkaloid-based multi-target strategies in treating NDs and calls for further research to understand their clinical applications fully. Future studies should focus on finding neuroprotective alkaloids, investigating their mechanisms, and evaluating their therapeutic potential. Understanding how alkaloids interact with key pathways in NDs is essential for developing effective therapies.

Defective Wnt signaling is found to be associated with various neurodegenerative diseases. In the canonical pathway, the Frizzled receptor (Fzd) and the lipoprotein receptor-related proteins 5/6 (LRP5/LRP6) create a seven-pass transmembrane receptor complex to which the Wnt ligands bind. This interaction causes the tumor suppressor adenomatous polyposis coli gene product (APC), casein kinase 1 (CK1), and GSK-3β (glycogen synthase kinase-3 beta) to be recruited by the scaffold protein Dishevelled (Dvl), which in turn deactivates the β-catenin destruction complex. This inactivation stops the destruction complex from phosphorylating β-catenin. As a result, β-catenin first builds up in the cytoplasm and then migrates into the nucleus, where it binds to the Lef/Tcf transcription factor to activate the transcription of more than 50 Wnt target genes, including those involved in cell growth, survival, differentiation, neurogenesis, and inflammation. The treatments that are currently available for neurodegenerative illnesses are most commonly not curative in nature but are only symptomatic. According to all available research, restoring Wnt/β-catenin signaling in the brains of patients with neurodegenerative disorders, particularly Alzheimer's and Parkinson's disease, would improve the condition of several patients with neurological disorders. The importance of Wnt activators and modulators in patients with such illnesses is to mainly restore rather than overstimulate the Wnt/β-catenin signaling, thereby reestablishing the equilibrium between Wnt-OFF and Wnt-ON states. In this review, we have tried to summarize the significance of the Wnt canonical pathway in the pathophysiology of certain neurodegenerative diseases, such as Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis, and other similar diseases, and as to how can it be restored in these patients.