Palgi, M. | bioRxiv Science

bioRxiv2021

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

Alzheimers 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 (A{beta}) 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, -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. Significance statementAlzheimers disease (AD) is a major biomedical concern that requires novel effective prevention and treatment approaches. An early determinant of AD pathology is dysregulated copper metabolism, which initiates the amyloid cascade, induces oxidative stress and impairs the functioning of cellular copper proteins, all contributing to the development of neurodegeneration. We suggest that the natural copper chelator -lipoic acid (LA) can normalize impaired copper metabolism in AD. We demonstrate that LA promotes the influx of copper into SH-SY5Y cells in a dose-dependent manner. Moreover, we show that LA alleviates the disease phenotype in a Drosophila melanogaster model of AD. Together with previously published data, these results support the hypothesis that LA has the potential for the prevention and treatment of AD.

neuroscience↗

bioRxiv2019

Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of synaptic proteome

Mammalian Transcription Factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities like Pitt-Hopkins syndrome (PTHS). Here we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed in the Drosophila brain structures associated with learning and memory, the mushroom bodies. Furthermore, silencing of da in mushroom body neurons impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and discs large 1 (dlg1) suggesting the involvement of Da in memory formation. Here we demonstrate that Syn and dlg1 are direct target genes of Da in adult Drosophila heads, since Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels of Syn and dlg1 mRNA. Silencing of da also affects negative geotaxis of the adult flies suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulates Drosophila larval memory and adult negative geotaxis possibly via its synaptic target genes Syn and dlg1. These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics.\n\nSummary statementHuman TCF4, a bHLH transcription factor, is associated with intellectual disability and schizophrenia. Here we propose a Drosophila model for human disease studies using TCF4 orthologue in fruit fly, Daughterless.

neuroscience↗