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Genes associated with amyloid-beta-induced inflammasome-mediated neuronal death identified using functional gene trap mutagenesis approach

Yap JKY, Pickard BS, Gan SY, Chan EWL

Int J Biochem Cell Biol, 2021 07;136:106014.
PMID: 34022435 DOI: 10.1016/j.biocel.2021.106014

Alzheimer's disease is an irreversible neurodegenerative disease, which accounts for most dementia cases. Neuroinflammation is increasingly recognised for its roles in Alzheimer's disease pathogenesis which, in part, links amyloid-beta to neuronal death. Neuroinflammatory signalling can be exhibited by neurons themselves, potentially leading to widespread neuronal cell death, although neuroinflammation is commonly associated with glial cells. The presence of the inflammasomes such as nucleotide-binding leucine-rich repeat receptors protein 1 in neurons accelerates amyloid-beta -induced neuroinflammation and has been shown to trigger neuronal pyroptosis in murine Alzheimer's disease models. However, the pathways involved in amyloid-beta activation of inflammasomes have yet to be elucidated. In this study, a gene trap mutagenesis approach was utilised to resolve the genes functionally involved in inflammasome signalling within neurons, and the mechanism behind amyloid-beta-induced neuronal death. The results indicate that amyloid-beta significantly accelerated neuroinflammatory cell death in the presence of a primed inflammasome (the NLR family pyrin domain-containing 1). The mutagenesis screen discovered the atypical mitochondrial Ras homolog family member T1 as a significant contributor to amyloid-beta-induced inflammasome -mediated neuronal death. The mutagenesis screen also identified two genes involved in transforming growth factor beta signalling, namely Transforming Growth Factor Beta Receptor 1 and SNW domain containing 1. Additionally, a gene associated with cytoskeletal reorganisation, SLIT-ROBO Rho GTPase Activating Protein 3 was found to be neuroprotective. In conclusion, these genes could play important roles in inflammasome signalling in neurons, which makes them promising therapeutic targets for future drug development against neuroinflammation in Alzheimer's disease.

Matched MeSH terms: Amyloid beta-Peptides/pharmacology*
Natural Polyphenols in the Treatment of Alzheimer's Disease

Syarifah-Noratiqah SB, Naina-Mohamed I, Zulfarina MS, Qodriyah HMS

Curr Drug Targets, 2018;19(8):927-937.
PMID: 28356027 DOI: 10.2174/1389450118666170328122527

Neurodegenerative disease is an incurable disease which involves the degeneration or death of the nerve cells. Alzheimer's Disease (AD) is a neurodegenerative disease discovered in 1906 by Alois Alzheimer, a German clinical psychiatrist and neuroanatomist. The main pathological hallmarks of this disease are the formation of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangle (NFT). The accumulation of the amyloid protein aggregates in the brain of AD patients leads to oxidative stress and inflammation. Other postulated reasons for the development of this disease are cholinergic depletion and excessive glutamatergic neurotransmission. The current drugs approved and marketed for the treatment of AD are cholinesterase inhibitors (ChEIs) and N-methyl-Daspartate (NMDA) receptor antagonists. The function of ChEIs is to avoid cholinergic depletion; whereas the function of NMDA receptor antagonist is to block excessive glutamatergic neurotransmission. Unfortunately, the current drugs prescribed for AD show only modest improvement in terms of symptomatic relief and delay the progression of the disease. This review will discuss about several polyphenolic compounds as potential natural treatment options for AD. Three compounds are highlighted in this review - Curcumin (Cur), Resveratrol (Rsv) and Epigallocatechin-3- gallate (EGCG). These compounds have huge potential for AD treatment, especially due to their low frequency of adverse events. However, the current conventional pharmaceutical drugs remain as the mainstay of treatment for AD.

Matched MeSH terms: Amyloid beta-Peptides/metabolism
Fulltext Current Concepts of Neurodegenerative Mechanisms in Alzheimer's Disease

Magalingam KB, Radhakrishnan A, Ping NS, Haleagrahara N

Biomed Res Int, 2018;2018:3740461.
PMID: 29707568 DOI: 10.1155/2018/3740461

Neurodegenerative diseases are hereditary or sporadic conditions that result in the progressive loss of the structure and function of neurons as well as neuronal death. Although a range of diseases lie under this umbrella term, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases that affect a large population around the globe. Alzheimer's disease is characterized by the abnormal accumulation of extracellular amyloid-β plaques and intraneuronal neurofibrillary tangles in brain regions and manifests as a type of dementia in aged individuals that results in memory loss, multiple cognitive abnormalities, and intellectual disabilities that interfere with quality of life. Since the discovery of AD, a wealth of new information has emerged that delineates the causes, mechanisms of disease, and potential therapeutic agents, but an effective remedy to cure the diseases has not been identified yet. This could be because of the complexity of the disease process, as it involves various contributing factors that include environmental factors and genetic predispositions. This review summarizes the current understanding on neurodegenerative mechanisms that lead to the emergence of the pathology of AD.

Matched MeSH terms: Amyloid beta-Peptides/metabolism*
Merging memantine and ferulic acid to probe connections between NMDA receptors, oxidative stress and amyloid-β peptide in Alzheimer's disease

Rosini M, Simoni E, Caporaso R, Basagni F, Catanzaro M, Abu IF, et al.

Eur J Med Chem, 2019 Oct 15;180:111-120.
PMID: 31301562 DOI: 10.1016/j.ejmech.2019.07.011

N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid β peptide (Aβ) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aβ neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC50 = 6.9 μM). In addition, at 10 μM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aβ production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aβ burden and oxidative damage.

Matched MeSH terms: Amyloid beta-Peptides/antagonists & inhibitors*; Amyloid beta-Peptides/metabolism
A critical role of TRPM2 channel in Aβ42 -induced microglial activation and generation of tumor necrosis factor-α

Alawieyah Syed Mortadza S, Sim JA, Neubrand VE, Jiang LH

Glia, 2018 03;66(3):562-575.
PMID: 29143372 DOI: 10.1002/glia.23265

Amyloid β (Aβ)-induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin-related 2 (TRPM2) channel in Aβ-induced neuroinflammation, but how Aβ induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which Aβ42 activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor-α (TNF-α), a key cytokine implicated in AD. Exposure to 10-300 nM Aβ42 induced concentration-dependent microglial activation and generation of TNF-α that were ablated by genetically deleting (TRPM2 knockout ;TRPM2-KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in Aβ42 -induced microglial activation and generation of TNF-α. Mechanistically, Aβ42 activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase-1 (PARP-1). Aβ42 -induced generation of ROS and activation of PARP-1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). Aβ42 -induced activation of PARP-1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. Aβ42 -induced activation of PARP-1 was attenuated by TRPM2-KO and moreover, the remaining PARP-1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX-mediated generation of ROS and subsequent activation of PARP-1 play a role in Aβ42 -induced TRPM2 channel activation and TRPM2-dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP-1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying Aβ-induced AD-related neuroinflammation.

Matched MeSH terms: Amyloid beta-Peptides/administration & dosage; Amyloid beta-Peptides/metabolism*
Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity

Bukhari SN, Jantan I, Masand VH, Mahajan DT, Sher M, Naeem-ul-Hassan M, et al.

Eur J Med Chem, 2014 Aug 18;83:355-65.
PMID: 24980117 DOI: 10.1016/j.ejmech.2014.06.034

A series of novel carbonyl compounds was synthesized by a simple, eco-friendly and efficient method. These compounds were screened for anti-oxidant activity, in vitro cytotoxicity and for inhibitory activity for acetylcholinesterase and butyrylcholinesterase. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. Among them, compound 14 exhibited strong free radical scavenging activity (18.39 μM) while six compounds (1, 3, 4, 13, 14, and 19) were found to be the most protective against Aβ-induced neuronal cell death in PC12 cells. Compounds 4 and 14, containing N-methyl-4-piperidone linker, showed high acetylcholinesterase inhibitory activity as compared to reference drug donepezil. Molecular docking and QSAR (Quantitative Structure-Activity Relationship) studies were also carried out to determine the structural features that are responsible for the acetylcholinesterase and butyrylcholinesterase inhibitory activity.

Matched MeSH terms: Amyloid beta-Peptides/toxicity*
Thymoquinone prevents β-amyloid neurotoxicity in primary cultured cerebellar granule neurons

Ismail N, Ismail M, Mazlan M, Latiff LA, Imam MU, Iqbal S, et al.

Cell Mol Neurobiol, 2013 Nov;33(8):1159-69.
PMID: 24101432 DOI: 10.1007/s10571-013-9982-z

Thymoquinone (TQ), a bioactive constituent of Nigella sativa Linn (N. sativa) has demonstrated several neuropharmacological attributes. In the present study, the neuroprotective properties of TQ were investigated by studying its anti-apoptotic potential to diminish β-amyloid peptide 1-40 sequence (Aβ1-40)-induced neuronal cell death in primary cultured cerebellar granule neurons (CGNs). The effects of TQ against Aβ1-40-induced neurotoxicity, morphological damages, DNA condensation, the generation of reactive oxygen species, and caspase-3, -8, and -9 activation were investigated. Pretreatment of CGNs with TQ (0.1 and 1 μM) and subsequent exposure to 10 μM Aβ1-40 protected the CGNs against the neurotoxic effects of the latter. In addition, the CGNs were better preserved with intact cell bodies, extensive neurite networks, a loss of condensed chromatin and less free radical generation than those exposed to Aβ1-40 alone. TQ pretreatment inhibited Aβ1-40-induced apoptosis of CGNs via both extrinsic and intrinsic caspase pathways. Thus, the findings of this study suggest that TQ may prevent neurotoxicity and Aβ1-40-induced apoptosis. TQ is, therefore, worth studying further for its potential to reduce the risks of developing Alzheimer's disease.

Matched MeSH terms: Amyloid beta-Peptides/toxicity*
Danshen (Salvia miltiorrhiza) water extract shows potential neuroprotective effects in Caenorhabditis elegans

Yuen CW, Murugaiyah V, Najimudin N, Azzam G

J Ethnopharmacol, 2021 Feb 10;266:113418.
PMID: 32991971 DOI: 10.1016/j.jep.2020.113418

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen, is a traditional Chinese medicine obtained from the dried root and rhizome of Salvia miltiorrhiza Bunge. It is known to be used for neurological disorder including for Alzheimer's disease (AD). This study uncovers the effect of Danshen water extract on the Alzheimer's disease model of C.elegans.
MATERIAL AND METHODS: The composition of Danshen water extract was determined using (High Performance Liquid Chromatography (HPLC). Then Thioflavin T assay was used to determined if Danshen water extract could prevent the aggregation of amyloid-β peptide (Aβ). Alzheimer's disease C.elegans model was used to determine the effect of Danshen water extract. Finally, the reactive oxygen species (ROS) was determined using the 2,7-dichlorofuorescein diacetate method.
RESULTS: In this study, we found that standardized Danshen water extract that contains danshensu (1.26%), salvianolic acid A (0.35%) and salvianolic acid B (2.21%) are able to bind directly to Aβ and prevents it from aggregating. The IC50 for the inhibition of Aβ aggregation by Danshen water extract was 0.5 mg/ml. In the AD model of C.elegans, Danshen water extract managed to alleviates the paralysis phenotype. Furthermore, the administration of Danshen water extract displayed antioxidant properties toward the Aβ-induced oxidative stress.
CONCLUSIONS: AD is a widespread neurodegenerative disease attributed to the accumulation of extracellular plaques comprising Aβ. Danshen water extract could significantly reduce the progress of paralysis in the AD model of C. elegans, showing promising results with its antioxidant properties. It can be concluded that Danshen water extract could potentially serve as a therapeutic for AD.

Matched MeSH terms: Amyloid beta-Peptides/metabolism
Therapeutic potential of neurogenesis and melatonin regulation in Alzheimer's disease

Mihardja M, Roy J, Wong KY, Aquili L, Heng BC, Chan YS, et al.

Ann N Y Acad Sci, 2020 10;1478(1):43-62.
PMID: 32700392 DOI: 10.1111/nyas.14436

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the hallmark pathologies of amyloid-beta plaques and neurofibrillary tangles. Symptoms of this devastating disease include behavioral changes and deterioration of higher cognitive functions. Impairment of neurogenesis has also been shown to occur in AD, which adversely impacts new neuronal cell growth, differentiation, and survival. This impairment possibly results from the cumulative effects of the various pathologies of AD. Preclinical studies have suggested that the administration of melatonin-the pineal hormone primarily responsible for the regulation of the circadian rhythm-targets the effects of AD pathologies and improves cognitive impairment. It is postulated that by mitigating the effect of these pathologies, melatonin can also rescue neurogenesis impairment. This review aims to explore the effect of AD pathologies on neurogenesis, as well as the mechanisms by which melatonin is able to ameliorate AD pathologies to potentially promote neurogenesis.

Matched MeSH terms: Amyloid beta-Peptides/genetics*
Fulltext REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease

Meyer K, Feldman HM, Lu T, Drake D, Lim ET, Ling KH, et al.

Cell Rep, 2019 01 29;26(5):1112-1127.e9.
PMID: 30699343 DOI: 10.1016/j.celrep.2019.01.023

The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.

Matched MeSH terms: Amyloid beta-Peptides/metabolism
Fulltext Pharmaceutical Potential of Casein-Derived Tripeptide Met-Lys-Pro: Improvement in Cognitive Impairments and Suppression of Inflammation in APP/PS1 Mice

Matsuzaki Tada A, Hamezah HS, Pahrudin Arrozi A, Abu Bakar ZH, Yanagisawa D, Tooyama I

J Alzheimers Dis, 2022;89(3):835-848.
PMID: 35964178 DOI: 10.3233/JAD-220192

BACKGROUND: Tripeptide Met-Lys-Pro (MKP), a component of casein hydrolysates, has effective angiotensin-converting enzyme (ACE) inhibitory activity. Brain angiotensin II enzyme activates the NADPH oxidase complex via angiotensin II receptor type 1 (AT1) and enhances oxidative stress injury. ACE inhibitors improved cognitive function in Alzheimer's disease (AD) mouse models and previous clinical trials. Thus, although undetermined, MKP may be effective against pathological amyloid-β (Aβ) accumulation-induced cognitive impairment.
OBJECTIVE: The current study aimed to investigate the potential of MKP as a pharmaceutical against AD by examining MKP's effect on cognitive function and molecular changes in the brain using double transgenic (APP/PS1) mice.
METHODS: Experimental procedures were conducted in APP/PS1 mice (n = 38) with a C57BL/6 background. A novel object recognition test was used to evaluate recognition memory. ELISA was used to measure insoluble Aβ40, Aβ42, and TNF-α levels in brain tissue. Immunohistochemical analysis allowed the assessment of glial cell activation in MKP-treated APP/PS1 mice.
RESULTS: The novel object recognition test revealed that MKP-treated APP/PS1 mice showed significant improvement in recognition memory. ELISA of brain tissue showed that MKP significantly reduced insoluble Aβ40, Aβ42, and TNF-α levels. Immunohistochemical analysis indicated the suppression of the marker for microglia and reactive astrocytes in MKP-treated APP/PS1 mice.
CONCLUSION: Based on these results, we consider that MKP could ameliorate pathological Aβ accumulation-induced cognitive impairment in APP/PS1 mice. Furthermore, our findings suggest that MKP potentially contributes to preventing cognitive decline in AD.

Matched MeSH terms: Amyloid beta-Peptides/therapeutic use
Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer's disease

Tan FHP, Ting ACJ, Leow BG, Najimudin N, Watanabe N, Azzam G

J Ethnopharmacol, 2021 Oct 28;279:114389.
PMID: 34217797 DOI: 10.1016/j.jep.2021.114389

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen water extract (DWE), obtained from the Salvia miltiorrhiza Bunge (Family Lamiaceae) root, is usually employed in Chinese traditional medicine as treatment to cardiovascular ailments and cerebrovascular diseases. Intriguingly, the extract was also found to contain vast beneficial properties in Alzheimer's disease (AD) treatment.
AIM OF THE STUDY: Alzheimer's disease is the most significant type of neurodegenerative disorder plaguing societies globally. Its pathogenesis encompasses the hallmark aggregation of amyloid-beta (Aβ). Of all the Aβ oligomers formed in the brain, Aβ42 is the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to attenuate Aβ42's toxic effects.
METHODS: The composition of DWE was determined via Ultra-Performance Liquid Chromatography (UPLC). DWE, SalA and SalB were first verified for their capability to diminish Aβ42 fibrillation using an in vitro activity assay. Since Aβ42 aggregation results in neuronal degeneration, the potential Aβ42 inhibitors were next evaluated on Aβ42-exposed PC12 neuronal cells. The Drosophila melanogaster AD model was then employed to determine the effects of DWE, SalA and SalB.
RESULTS: DWE, SalA and SalB were shown to be able to reduce fibrillation of Aβ42. When tested on PC12 neuronal cells, DWE, SalA and SalB ameliorated cells from cell death associated with Aβ42 exposure. Next, DWE and its components were tested on the Drosophila melanogaster AD model and their rescue effects were further characterized. The UPLC analysis showed that SalA and SalB were present in the brains and bodies of Drosophila after DWE feeding. When human Aβ42 was expressed, the AD Drosophila exhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of AD Drosophila and improved most of the mobility of AD Drosophila.
CONCLUSION: Collectively, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases.

Matched MeSH terms: Amyloid beta-Peptides/metabolism
Fulltext Comparative Effects of Alpha- and Gamma-Tocopherol on Mitochondrial Functions in Alzheimer's Disease In Vitro Model

Pahrudin Arrozi A, Shukri SNS, Wan Ngah WZ, Mohd Yusof YA, Ahmad Damanhuri MH, Jaafar F, et al.

Sci Rep, 2020 06 02;10(1):8962.
PMID: 32488024 DOI: 10.1038/s41598-020-65570-4

Vitamin E acts as an antioxidant and reduces the level of reactive oxygen species (ROS) in Alzheimer's disease (AD). Alpha-tocopherol (ATF) is the most widely studied form of vitamin E besides gamma-tocopherol (GTF) which also shows beneficial effects in AD. The levels of amyloid-beta (Aβ) and amyloid precursor protein (APP) increased in the brains of AD patients, and mutations in the APP gene are known to enhance the production of Aβ. Mitochondrial function was shown to be affected by the increased level of Aβ and may induce cell death. Here, we aimed to compare the effects of ATF and GTF on their ability to reduce Aβ level, modulate mitochondrial function and reduce the apoptosis marker in SH-SY5Y cells stably transfected with the wild-type or mutant form of the APP gene. The Aβ level was measured by ELISA, the mitochondrial ROS and ATP level were quantified by fluorescence and luciferase assay respectively whereas the complex V enzyme activity was measured by spectrophotometry. The expressions of genes involved in the regulation of mitochondrial membrane permeability such as voltage dependent anion channel (VDAC1), adenine nucleotide translocase (ANT), and cyclophilin D (CYPD) were determined by quantitative real-time polymerase chain reaction (qRT-PCR), while the expressions of cyclophilin D (CypD), cytochrome c, Bcl2 associated X (BAX), B cell lymphoma-2 (Bcl-2), and pro-caspase-3 were determined by western blot. Our results showed that mitochondrial ROS level was elevated accompanied by decreased ATP level and complex V enzyme activity in SH-SY5Y cells expressing the mutant APP gene (p

Matched MeSH terms: Amyloid beta-Peptides/metabolism
Fulltext The Biological Activities of Oleocanthal from a Molecular Perspective

Pang KL, Chin KY

Nutrients, 2018 May 06;10(5).
PMID: 29734791 DOI: 10.3390/nu10050570

Oleocanthal is a minor constituent of olive oil with strong anti-inflammatory activities. Since the pathogenesis of many chronic diseases involves inflammatory and oxidative components, oleocanthal is a promising agent to prevent these conditions. This review aimed to summarise the current beneficial health effects of oleocanthal and the molecular basis of its biological actions. The anti-inflammatory, antioxidative, antimicrobial, anticancer and neuroprotective activities of oleocanthal have been examined by previous studies. Of these, studies on the anticancer effects have been the most extensive. Oleocanthal was reported to suppress melanoma, breast, liver, and colon cancer cells. Neurological studies focused on the effects of oleocanthal against Alzheimer’s disease. Oleocanthal improved clearance of the amyloid beta protein from neurons and reduced the inflammation of astrocytes. Despite the positive results, validation of the biological effects of oleocanthal in animal disease models is limited and should be emphasized in the future. As a conclusion, oleocanthal may act together with other bioactive compounds in olive oil to achieve its therapeutic potential. The use of oleocanthal alone as a single therapeutic measure awaits validation from future studies.

Matched MeSH terms: Amyloid beta-Peptides/metabolism
Epigenetic Changes and Its Intervention in Age-Related Neurodegenerative Diseases

Mohd Murshid N, Aminullah Lubis F, Makpol S

Cell Mol Neurobiol, 2020 Oct 19.
PMID: 33074454 DOI: 10.1007/s10571-020-00979-z

Epigenetic mechanisms involving the modulation of gene activity without modifying the DNA bases are reported to have lifelong effects on mature neurons in addition to their impact on synaptic plasticity and cognition. Histone methylation and acetylation are involved in synchronizing gene expression and protein function in neuronal cells. Studies have demonstrated in experimental models of neurodegenerative disorders that manipulations of these two mechanisms influence the susceptibility of neurons to degeneration and apoptosis. In Alzheimer's disease (AD), the expression of presenilin 1 (PSEN1) is markedly increased due to decreased methylation at CpG sites, thus promoting the accumulation of toxic amyloid-β (Aβ) peptide. In Parkinson's disease (PD), dysregulation of α-synuclein (SNCA) expression is presumed to occur via aberrant methylation at CpG sites, which controls the activation or suppression of protein expression. Mutant Huntingtin (mtHTT) alters the activity of histone acetyltransferases (HATs), causing the dysregulation of transcription observed in most Huntington's disease (HD) cases. Folate, vitamin B6, vitamin B12, and S-adenosylmethionine (SAM) are vital cofactors involved in DNA methylation modification; 5-azacytidine (AZA) is the most widely studied DNA methyltransferase (DNMT) inhibitor, and dietary polyphenols are DNMT inhibitors in vitro. Drug intervention is believed to reverse the epigenetic mechanisms to serve as a regulator in neuronal diseases. Nevertheless, the biochemical effect of the drugs on brain function and the underlying mechanisms are not well understood. This review focuses on further discussion of therapeutic targets, emphasizing the potential role of epigenetic factors including histone and DNA modifications in the diseases.

Matched MeSH terms: Amyloid beta-Peptides
Butyrylcholinesterase: A Multifaceted Pharmacological Target and Tool

Ha ZY, Mathew S, Yeong KY

Curr Protein Pept Sci, 2020;21(1):99-109.
PMID: 31702488 DOI: 10.2174/1389203720666191107094949

Butyrylcholinesterase is a serine hydrolase that catalyzes the hydrolysis of esters in the body. Unlike its sister enzyme acetylcholinesterase, butyrylcholinesterase has a broad substrate scope and lower acetylcholine catalytic efficiency. The difference in tissue distribution and inhibitor sensitivity also points to its involvement external to cholinergic neurotransmission. Initial studies on butyrylcholinesterase showed that the inhibition of the enzyme led to the increment of brain acetylcholine levels. Further gene knockout studies suggested its involvement in the regulation of amyloid-beta, a brain pathogenic protein. Thus, it is an interesting target for neurological disorders such as Alzheimer's disease. The substrate scope of butyrylcholinesterase was recently found to include cocaine, as well as ghrelin, the "hunger hormone". These findings led to the development of recombinant butyrylcholinesterase mutants and viral gene therapy to combat cocaine addiction, along with in-depth studies on the significance of butyrylcholinesterase in obesity. It is observed that the pharmacological impact of butyrylcholinesterase increased in tandem with each reported finding. Not only is the enzyme now considered an important pharmacological target, it is also becoming an important tool to study the biological pathways in various diseases. Here, we review and summarize the biochemical properties of butyrylcholinesterase and its roles, as a cholinergic neurotransmitter, in various diseases, particularly neurodegenerative disorders.

Matched MeSH terms: Amyloid beta-Peptides/antagonists & inhibitors; Amyloid beta-Peptides/genetics; Amyloid beta-Peptides/metabolism
Fulltext Effects of Amyloid Precursor Protein Overexpression on NF-κB, Rho-GTPase and Pro-Apoptosis Bcl-2 Pathways in Neuronal Cells

Chan HH, Leong YQ, Voon SM, Pan ML, Leong CO, Lim CL, et al.

Rep Biochem Mol Biol, 2021 Jan;9(4):417-425.
PMID: 33969135 DOI: 10.52547/rbmb.9.4.417

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive dysfunction. Previous studies have suggested that amyloid plaques, mainly comprising of amyloid-beta peptides, play a pivotal role in AD pathophysiology. This study focuses on the evaluation of the effects of amyloid precursor protein (APP) overexpression on NF-κB, Rho-GTPase and Bcl-2 mediated pro-apoptotic pathways in neuronal cells.
Methods: A lentiviral transduction system was used to generate SH-SY5Y cells overexpressing APP. Immunoblotting was conducted to determine expression levels of NF-κB, Rho-GTPase, and Bcl-2 family proteins in the APP overexpressed cells.
Results: In the NF-κB signaling pathway, APP-overexpressing SH-SY5Y cells showed that there was a reduction of p-NF-κB (p< 0.05) and IKKα. Subsequently, there was upregulation of protein expression of NF-Κb, IKKβ and IκBα. On the other hand, protein expression of RhoC (p< 0.05) and Rac1/2/3 was upregulated as compared to the control group. Meanwhile, a decrease in RhoA, Cdc42 (p< 0.05) and p-Rac1/cdc42 protein levels was observed in the APP-overexpressed group. Lastly, in the pro-apoptotic pathway, the expression of Bcl-2, Bid, Bok and Puma (p< 0.05) was up regulated in the APP-overexpressed group. Downregulation of Bad and Bim expression was observed in the APP-overexpressed as compared to the control group, and Bax expression remained unchanged in the APP-overexpressed group.
Conclusion: APP overexpression regulated signaling in the NF-κB, Rho-GTPase and Bcl-2 family pathways in neuronal cells, suggesting that these are involved in promoting neuronal survival and modulating synaptic plasticity in AD. However, further studies are essential to elucidate the APP-mediated mechanism of action.

Matched MeSH terms: Amyloid beta-Peptides
Fulltext Predisposition to Alzheimer's and Age-Related Brain Pathologies by PM2.5 Exposure: Perspective on the Roles of Oxidative Stress and TRPM2 Channel

Wang L, Wei LY, Ding R, Feng Y, Li D, Li C, et al.

Front Physiol, 2020;11:155.
PMID: 32174842 DOI: 10.3389/fphys.2020.00155

Accumulating epidemiological evidence supports that chronic exposure to ambient fine particular matters of <2.5 μm (PM2.5) predisposes both children and adults to Alzheimer's disease (AD) and age-related brain damage leading to dementia. There is also experimental evidence to show that PM2.5 exposure results in early onset of AD-related pathologies in transgenic AD mice and development of AD-related and age-related brain pathologies in healthy rodents. Studies have also documented that PM2.5 exposure causes AD-linked molecular and cellular alterations, such as mitochondrial dysfunction, synaptic deficits, impaired neurite growth, neuronal cell death, glial cell activation, neuroinflammation, and neurovascular dysfunction, in addition to elevated levels of amyloid β (Aβ) and tau phosphorylation. Oxidative stress and the oxidative stress-sensitive TRPM2 channel play important roles in mediating multiple molecular and cellular alterations that underpin AD-related cognitive dysfunction. Documented evidence suggests critical engagement of oxidative stress and TRPM2 channel activation in various PM2.5-induced cellular effects. Here we discuss recent studies that favor causative relationships of PM2.5 exposure to increased AD prevalence and AD- and age-related pathologies, and raise the perspective on the roles of oxidative stress and the TRPM2 channel in mediating PM2.5-induced predisposition to AD and age-related brain damage.

Matched MeSH terms: Amyloid beta-Peptides
Time- and dose-related effects of amyloid beta1-40 on retina and optic nerve morphology in rats

Mohd Lazaldin MA, Iezhitsa I, Agarwal R, Bakar NS, Agarwal P, Mohd Ismail N

Int J Neurosci, 2018 Oct;128(10):952-965.
PMID: 29488424 DOI: 10.1080/00207454.2018.1446953

PURPOSE: Amyloid beta (Aβ) is known to contribute to the pathophysiology of retinal neurodegenerative diseases such as glaucoma. Effects of intravitreal Aβ(1-42) on retinal and optic nerve morphology in animal models have widely been studied but not those of Aβ(1-40). Hence, we evaluated the time- and dose-related effects of intravitreal Aβ(1-40) on retinal and optic nerve morphology. Since oxidative stress and brain derived neurotrophic factor (BDNF) are associated with Aβ-induced neuronal damage, we also studied dose and time-related effects of Aβ(1-40) on retinal oxidative stress and BDNF levels.
MATERIALS AND METHODS: Five groups of rats were intravitreally administered with vehicle or Aβ(1-40) in doses of 1.0, 2.5, 5 and 10 nmol. Animals were sacrificed and eyes were enucleated at weeks 1, 2 and 4 post-injection. The retinae were subjected to morphometric analysis and TUNEL staining. Optic nerve sections were stained with toluidine blue and were graded for neurodegenerative effects. The estimation of BDNF and markers of oxidative stress in retina were done using ELISA technique.
RESULTS AND CONCLUSIONS: It was observed that intravitreal Aβ(1-40) causes significant retinal and optic nerve damage up to day 14 post-injection and there was increasing damage with increase in dose. However, on day 30 post-injection both the retinal and optic nerve morphology showed a trend towards normalization. The observations made for retinal cell apoptosis, retinal glutathione, superoxide dismutase activity and BDNF were in accordance with those of morphological changes with deterioration till day 14 and recovery by day 30 post-injection. The findings of this study may provide a guide for selection of appropriate experimental conditions for future studies.

Matched MeSH terms: Amyloid beta-Peptides
Fulltext Role of neurotoxicants in the pathogenesis of Alzheimer's disease: a mechanistic insight

Nisa FY, Rahman MA, Hossen MA, Khan MF, Khan MAN, Majid M, et al.

Ann Med, 2021 Dec;53(1):1476-1501.
PMID: 34433343 DOI: 10.1080/07853890.2021.1966088

Alzheimer's disease (AD) is the most conspicuous chronic neurodegenerative syndrome, which has become a significant challenge for the global healthcare system. Multiple studies have corroborated a clear association of neurotoxicants with AD pathogenicity, such as Amyloid beta (Aβ) proteins and neurofibrillary tangles (NFTs), signalling pathway modifications, cellular stress, cognitive dysfunctions, neuronal apoptosis, neuroinflammation, epigenetic modification, and so on. This review, therefore, aimed to address several essential mechanisms and signalling cascades, including Wnt (wingless and int.) signalling pathway, autophagy, mammalian target of rapamycin (mTOR), protein kinase C (PKC) signalling cascades, cellular redox status, energy metabolism, glutamatergic neurotransmissions, immune cell stimulations (e.g. microglia, astrocytes) as well as an amyloid precursor protein (APP), presenilin-1 (PSEN1), presenilin-2 (PSEN2) and other AD-related gene expressions that have been pretentious and modulated by the various neurotoxicants. This review concluded that neurotoxicants play a momentous role in developing AD through modulating various signalling cascades. Nevertheless, comprehension of this risk agent-induced neurotoxicity is far too little. More in-depth epidemiological and systematic investigations are needed to understand the potential mechanisms better to address these neurotoxicants and improve approaches to their risk exposure that aid in AD pathogenesis.Key messagesInevitable cascade mechanisms of how Alzheimer's Disease-related (AD-related) gene expressions are modulated by neurotoxicants have been discussed.Involvement of the neurotoxicants-induced pathways caused an extended risk of AD is explicited.Integration of cell culture, animals and population-based analysis on the clinical severity of AD is addressed.

Matched MeSH terms: Amyloid beta-Peptides

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