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Ageing and the gut-brain axis: lessons from the Drosophila model

Tan FHP, Shamsuddin S, Zainuddin A

Benef Microbes, 2023 Dec 13;14(6):591-607.
PMID: 38350490 DOI: 10.1163/18762891-20230056

The steady decline of physiological function and increased vulnerability to age-related disorders are two features of the complicated biological process of ageing. As a key organ for nutrient absorption, metabolism, and immunological regulation, the gut plays a major part in the ageing process. Drosophila melanogaster, a well-established model organism, has emerged as a significant tool for exploring the intricate rapport between the gut and ageing. Through the use of Drosophila models, the physiological and molecular elements of the gut-brain axis have been thoroughly explored. These models have also provided insights into the mechanisms by which gut health impacts ageing and age-related illnesses. Drosophila's gut microbiota experience dysbiosis with age which has been linked to age-related diseases. To prevent this and promote healthy ageing in Drosophila, gut microbiota modification methods, such as dietary restriction in tandem with time-restricted feeding, administration of pro-, pre- and synbiotics, as well as pharmaceutical interventions have been generated with positive impacts. The article also covers the drawbacks and difficulties of investigating the gut via the Drosophila. Thus, with an emphasis on the lessons discovered from Drosophila research, this review provides an extensive description of the current studies on the role of the gut-brain axis in ageing and health.
Fulltext Drosophila melanogaster: Deciphering Alzheimer's Disease

Tan FHP, Azzam G

Malays J Med Sci, 2017 Mar;24(2):6-20.
PMID: 28894399 MyJurnal DOI: 10.21315/mjms2017.24.2.2

Alzheimer's disease (AD) is the most widespread neurodegenerative disorder worldwide. Its pathogenesis involves two hallmarks: aggregation of amyloid beta (Aβ) and occurrence of neurofibrillary tangles (NFTs). The mechanism behind the disease is still unknown. This has prompted the use of animal models to mirror the disease. The fruit fly, Drosophila melanogaster has garnered considerable attention as an organism to recapitulate human disorders. With the ability to monopolise a multitude of traditional and novel genetic tools, Drosophila is ideal for studying not only cellular aspects but also physiological and behavioural traits of human neurodegenerative diseases. Here, we discuss the use of the Drosophila model in understanding AD pathology and the insights gained in discovering drug therapies for AD.
Fulltext Microalgal Biomass as Feedstock for Bacterial Production of PHA: Advances and Future Prospects

Tan FHP, Nadir N, Sudesh K

Front Bioeng Biotechnol, 2022;10:879476.
PMID: 35646848 DOI: 10.3389/fbioe.2022.879476

The search for biodegradable plastics has become the focus in combating the global plastic pollution crisis. Polyhydroxyalkanoates (PHAs) are renewable substitutes to petroleum-based plastics with the ability to completely mineralize in soil, compost, and marine environments. The preferred choice of PHA synthesis is from bacteria or archaea. However, microbial production of PHAs faces a major drawback due to high production costs attributed to the high price of organic substrates as compared to synthetic plastics. As such, microalgal biomass presents a low-cost solution as feedstock for PHA synthesis. Photoautotrophic microalgae are ubiquitous in our ecosystem and thrive from utilizing easily accessible light, carbon dioxide and inorganic nutrients. Biomass production from microalgae offers advantages that include high yields, effective carbon dioxide capture, efficient treatment of effluents and the usage of infertile land. Nevertheless, the success of large-scale PHA synthesis using microalgal biomass faces constraints that encompass the entire flow of the microalgal biomass production, i.e., from molecular aspects of the microalgae to cultivation conditions to harvesting and drying microalgal biomass along with the conversion of the biomass into PHA. This review discusses approaches such as optimization of growth conditions, improvement of the microalgal biomass manufacturing technologies as well as the genetic engineering of both microalgae and PHA-producing bacteria with the purpose of refining PHA production from microalgal biomass.
Behavioural Effects and RNA-seq Analysis of Aβ42-Mediated Toxicity in a Drosophila Alzheimer's Disease Model

Tan FHP, Azzam G, Najimudin N, Shamsuddin S, Zainuddin A

Mol Neurobiol, 2023 Aug;60(8):4716-4730.
PMID: 37145377 DOI: 10.1007/s12035-023-03368-x

Alzheimer's disease (AD) is the most common neurological ailment worldwide. Its process comprises the unique aggregation of extracellular senile plaques composed of amyloid-beta (Aβ) in the brain. Aβ42 is the most neurotoxic and aggressive of the Aβ42 isomers released in the brain. Despite much research on AD, the complete pathophysiology of this disease remains unknown. Technical and ethical constraints place limits on experiments utilizing human subjects. Thus, animal models were used to replicate human diseases. The Drosophila melanogaster is an excellent model for studying both physiological and behavioural aspects of human neurodegenerative illnesses. Here, the negative effects of Aβ42-expression on a Drosophila AD model were investigated through three behavioural assays followed by RNA-seq. The RNA-seq data was verified using qPCR. AD Drosophila expressing human Aβ42 exhibited degenerated eye structures, shortened lifespan, and declined mobility function compared to the wild-type Control. RNA-seq revealed 1496 genes that were differentially expressed from the Aβ42-expressing samples against the control. Among the pathways that were identified from the differentially expressed genes include carbon metabolism, oxidative phosphorylation, antimicrobial peptides, and longevity-regulating pathways. While AD is a complicated neurological condition whose aetiology is influenced by a number of factors, it is hoped that the current data will be sufficient to give a general picture of how Aβ42 influences the disease pathology. The discovery of molecular connections from the current Drosophila AD model offers fresh perspectives on the usage of this Drosophila which could aid in the discovery of new anti-AD medications.
p-Coumaric acid attenuates the effects of Aβ42 in vitro and in a Drosophila Alzheimer's disease model

Tan FHP, Najimudin N, Watanabe N, Shamsuddin S, Azzam G

Behav Brain Res, 2023 Aug 24;452:114568.
PMID: 37414223 DOI: 10.1016/j.bbr.2023.114568

Alzheimer's disease (AD) is the most common neurodegenerative condition in civilizations worldwide. The distinctive occurrence of amyloid-beta (Aβ) accumulation into insoluble fibrils is part of the disease pathophysiology with Aβ42 being the most toxic and aggressive Aβ species. The polyphenol, p-Coumaric acid (pCA), has been known to boost a number of therapeutic benefits. Here, pCA's potential to counteract the negative effects of Aβ42 was investigated. First, pCA was confirmed to reduce Aβ42 fibrillation using an in vitro activity assay. The compound was next examined on Aβ42-exposed PC12 neuronal cells and was found to significantly decrease Aβ42-induced cell mortality. pCA was then examined using an AD Drosophila melanogaster model. Feeding of pCA partially reversed the rough eye phenotype, significantly lengthened AD Drosophila's lifespan, and significantly enhanced the majority of the AD Drosophila's mobility in a sex-dependent manner. The findings of this study suggest that pCA may have therapeutic benefits for AD.
Lactobacillus probiotics improved the gut microbiota profile of a Drosophila melanogaster Alzheimer's disease model and alleviated neurodegeneration in the eye

Tan FHP, Liu G, Lau SA, Jaafar MH, Park YH, Azzam G, et al.

Benef Microbes, 2020 Feb 19;11(1):79-89.
PMID: 32066253 DOI: 10.3920/BM2019.0086

Alzheimer's disease (AD) is a progressive disease and one of the most common forms of neurodegenerative disorders. Emerging evidence is supporting the use of various strategies that modulate gut microbiota to exert neurological and psychological changes. This includes the utilisation of probiotics as a natural and dietary intervention for brain health. Here, we showed the potential AD-reversal effects of Lactobacillus probiotics through feeding to our Drosophila melanogaster AD model. The administration of Lactobacillus strains was able to rescue the rough eye phenotype (REP) seen in AD-induced Drosophila, with a more prominent effect observed upon the administration of Lactobacillus plantarum DR7 (DR7). Furthermore, we analysed the gut microbiota of the AD-induced Drosophila and found elevated levels of Wolbachia. The administration of DR7 restored the gut microbiota diversity of AD-induced Drosophila with a significant reduction in Wolbachia's relative abundance, accompanied by an increase of Stenotrophomonas and Acetobacter. Through functional predictive analyses, Wolbachia was predicted to be positively correlated with neurodegenerative disorders, such as Parkinson's, Huntington's and Alzheimer's diseases, while Stenotrophomonas was negatively correlated with these neurodegenerative disorders. Altogether, our data exhibited DR7's ability to ameliorate the AD effects in our AD-induced Drosophila. Thus, we propose that Wolbachia be used as a potential biomarker for AD.
Ethyl caffeate ameliorated amyloid-beta42 protein-associated toxicity in PC12 cells and Drosophila melanogaster

Tan FHP, Hadri NAB, Najimudin N, Watanabe N, Azzam G

Geriatr Gerontol Int, 2021 Dec;21(12):1125-1130.
PMID: 34699118 DOI: 10.1111/ggi.14296

AIM: Alzheimer's disease (AD) is the most pervasive neurodegenerative disorder in societies globally. Till now, the mechanism behind this disease is still equivocal. Amyloid-beta42 protein (Aβ42), the most toxic and aggressive Aβ species, is the main focus of this study. The naturally occurring ethyl caffeate (EC) is associated with various medicinal properties. Here, EC was tested for its protective properties against Aβ42's toxic effects.
METHODS: As treatment of Aβ42 has been shown to cause neuronal cell death, EC was first screened with Aβ42-incubated PC12 neuronal cells. Next, the compound was tested on the Drosophila melanogaster AD model using the rough eye phenotype assay, lifespan assay and negative geotaxis assay.
RESULTS: EC ameliorated PC12 cells from cell death linked to Aβ42 exposure. Using Drosophila expressing human Aβ42, feeding of EC was able to partially rescue the rough eye phenotype, lengthen the lifespan of AD Drosophila and enhanced the mobility of middle-aged AD Drosophila.
CONCLUSION: Overall, the results of this study showed that EC might possess therapeutic properties for AD. Geriatr Gerontol Int 2021; 21: 1125-1130.
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.
3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-Carbonyl]Amino]Propanoic Acid (THICAPA) Is Protective Against Aβ42-Induced Toxicity In Vitro and in an Alzheimer's Disease Drosophila

Tan FHP, Ting ACJ, Najimudin N, Watanabe N, Shamsuddin S, Zainuddin A, et al.

J Gerontol A Biol Sci Med Sci, 2023 Oct 28;78(11):1944-1952.
PMID: 37453137 DOI: 10.1093/gerona/glad169

Alzheimer's disease (AD) is the most prevalent type of dementia globally. The accumulation of amyloid-beta (Aβ) extracellular senile plaques in the brain is one of the hallmark mechanisms found in AD. Aβ42 is the most damaging and aggressively aggregating Aβ isomer produced in the brain. Although Aβ42 has been extensively researched as a crucial peptide connected to the development of the characteristic amyloid fibrils in AD, the specifics of its pathophysiology are still unknown. Therefore, the main objective was to identify novel compounds that could potentially mitigate the negative effects of Aβ42. 3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carbonyl]amino]propanoic acid (THICAPA) was identified as a ligand for Aβ42 and for reducing fibrillary Aβ42 aggregation. THICAPA also improved cell viability when administered to PC12 neuronal cells that were exposed to Aβ42. Additionally, this compound diminished Aβ42 toxicity in the current AD Drosophila model by rescuing the rough eye phenotype, prolonging the life span, and enhancing motor functions. Through next-generation RNA-sequencing, immune response pathways were downregulated in response to THICAPA treatment. Thus, this study suggests THICAPA as a possible disease-modifying treatment for AD.
Fulltext Ageing, Drosophila melanogaster and Epigenetics

Halim MA, Tan FHP, Azlan A, Rasyid II, Rosli N, Shamsuddin S, et al.

Malays J Med Sci, 2020 May;27(3):7-19.
PMID: 32684802 MyJurnal DOI: 10.21315/mjms2020.27.3.2

Ageing is a phenomenon where the accumulation of all the stresses that alter the functions of living organisms, halter them from maintaining their physiological balance and eventually lead to death. The emergence of epigenetic tremendously contributed to the knowledge of ageing. Epigenetic changes in cells or tissues like deoxyribonucleic acid (DNA) methylation, modification of histone proteins, transcriptional modification and also the involvement of non-coding DNA has been documented to be associated with ageing. In order to study ageing, scientists have taken advantage of several potential organisms to aid them in their study. Drosophila melanogaster has been an essential model in establishing current understanding of the mechanism of ageing as they possess several advantages over other competitors like having homologues to more than 75% of human disease genes, having 50% of Drosophila genes are homologues to human genes and most importantly they are genetically amenable. Here, we would like to summarise the extant knowledge about ageing and epigenetic process and the role of Drosophila as an ideal model to study epigenetics in association with ageing process.