Genetic Dissection of Alzheimer’s Disease Using Drosophila Models

Jeon, Yong Jin; Lee, Jaeha; Choi, Byoungyun; Won, So Yoon; Cho, Kyoung Sang

doi:10.3390/ijms21030884

Cited by 29 publications

(12 citation statements)

References 250 publications

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“…We used the overexpression of APP or Aβ to model AD in flies (reviewed by (42)). For the ectopic overexpression in Drosophila , the two-component Gal4-upstream activating sequence (UAS) system is widely exploited (43).…”

Section: Resultsmentioning

confidence: 99%

α-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease

Metsla

Kirss

Laks

et al. 2021

Preprint

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Alzheimer′s disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-beta (Aβ) peptides. Multiple amyloid-targeting drug candidates have recently failed in clinical trials, which creates the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess extracellular copper levels. In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and searched for new copper-regulating ligands. We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in a SH-SY5Y-based neuronal cell model, and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster model of AD from developing AD phenotype, reflecting in decreased locomotor activity. Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD and supports the hypothesis that LA supplementation may serve as a promising cost-effective method for the prevention and/or treatment of AD.

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Section: Resultsmentioning

confidence: 99%

α-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease

Metsla

Kirss

Laks

et al. 2021

Preprint

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“…Numerous drugs have been tested to prevent and cure Alzheimer's disease in an animal model [2,48,49]. The symptoms in most AD animal models are onset in adults; therefore, targeted drugs are considered to act directly on AD via ameliorating AD-related symptoms, rather than slowing down aging to delay the onset of AD [3,50]. We will discuss relevant drugs and their targeted signaling pathways in detail as follows.…”

Section: Pharmacological Treatment Of Alzheimer's Disease Using Drosomentioning

confidence: 99%

“…Because of the complexity and the universality of neurodegeneration, studies involving its pathogenesis and treatment continue to invite a lot of attention from the scientific community [2]. Among all the neurodegenerative disorders, Alzheimer disease (AD) is the most common form of dementia, which causes cognitive deficits, memory loss, and behavioral alterations [3]. According to the World Alzheimer Report, about 50 million people worldwide were reported to have dementia in 2018.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Treatment of Alzheimer’s Disease: Insights from Drosophila melanogaster

Cheng

Song

et al. 2020

IJMS

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Aging is an ineluctable law of life. During the process of aging, the occurrence of neurodegenerative disorders is prevalent in the elderly population and the predominant type of dementia is Alzheimer’s disease (AD). The clinical symptoms of AD include progressive memory loss and impairment of cognitive functions that interfere with daily life activities. The predominant neuropathological features in AD are extracellular β-amyloid (Aβ) plaque deposition and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Because of its complex pathobiology, some tangible treatment can only ameliorate the symptoms, but not prevent the disease altogether. Numerous drugs during pre-clinical or clinical studies have shown no positive effect on the disease outcome. Therefore, understanding the basic pathophysiological mechanism of AD is imperative for the rational design of drugs that can be used to prevent this disease. Drosophila melanogaster has emerged as a highly efficient model system to explore the pathogenesis and treatment of AD. In this review we have summarized recent advancements in the pharmacological research on AD using Drosophila as a model species, discussed feasible treatment strategies and provided further reference for the mechanistic study and treatment of age-related AD.

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“…Further, do other neurodegenerative disease models display similar maturation defects, suggesting a developmental component to classical models of neurodegenerative disease and providing mechanistic insight into their progression and potential treatment. Current Drosophila Alzheimer’s models use overexpression of pathogenic forms of Tau or Aβ consistent with accumulations in humans ( 64 ) or neuron-specific RNAi ( 65 ). However, these approaches do not address how patient mutations in presenilin influence disease progression, or if loss-of-function recapitulates the phenotypes of Alzheimer’s-linked mutations ( 35, 66 ).…”

Section: Introductionmentioning

confidence: 99%

γ-secretase promotes postsynaptic maturation through the cleavage of a Wnt receptor

Restrepo

DePew

Moese

et al. 2020

Preprint

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An emerging feature of neurodegenerative disease is synaptic dysfunction and loss, leading to the suggestion that mechanisms required for synaptic maturation may be linked to disease. Synaptic maturation requires the transmission of signals between nascent synaptic sites and the nucleus, but how these signals are generated is not well understood. We posit that proteolytic cleavage of receptors, which enables their translocation to the nucleus, may be a shared molecular mechanism between the events that promote synaptic maturation and those linked to later-onset disorders of the nervous system, including neurodegenerative disease. Here we show during synaptic development, that cleavage of synaptic maturation molecules requires γ-secretase, a protein complex linked to Alzheimer’s Disease, a devastating neurodegenerative condition, is required for postsynaptic maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to appropriately recruit postsynaptic scaffolding and cytoskeletal proteins, and mutant larvae display behavioral deficits. At the NMJ, γ-secretase promotes synaptic maturation through the cleavage of the Wnt receptor Fz2, and the subsequent entry of its C-terminus into the nucleus. A developmental synaptic role for γ-secretase is also conserved in both the Drosophila central nervous system and mammalian cortical neuron dendrites. Finally, we found that similar maturation defects are evident in fly models for ALS, Alzheimer’s, Huntington’s, and Parkinson’s Diseases. The previously unknown, but conserved, role for γ-secretase coupled with its well-known role in neurodegenerative disease suggest that neurodevelopmental defects may be common to diverse neurodegenerative disease models.

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Genetic Dissection of Alzheimer’s Disease Using Drosophila Models

Cited by 29 publications

References 250 publications

α-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease

α-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer’s disease

Pharmacological Treatment of Alzheimer’s Disease: Insights from Drosophila melanogaster

γ-secretase promotes postsynaptic maturation through the cleavage of a Wnt receptor

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