A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

Using Drosophila amyloid toxicity models to study Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterised by a progressive loss of neurons, which manifests as gradual memory decline, followed by cognitive loss. Despite the significant progress in identifying novel biomarkers and understanding the prodromal pathology and symptomatology, AD remains a significant unmet clinical need. Lecanemab and aducanumab, the only Food and Drug Administration approved drugs to exhibit some disease-modifying clinical efficacy, target Aß amyloid, underscoring the importance of this protein in disease aetiology. Nevertheless, in the absence of a definitive cure, the utilisation of preclinical models remains imperative for the identification of novel therapeutic targets and the evaluation of potential therapeutic agents. Drosophila melanogaster is a model system that can be used as a research tool to investigate neurodegeneration and therapeutic interventions. The short lifespan, low price and ease of husbandry/rearing make Drosophila an advantageous model organism from a practical perspective. However, it is the highly conserved genome and similarity of Drosophila and human neurobiology which make flies a powerful tool to investigate neurodegenerative mechanisms. In addition, the ease of transgenic modifications allows for early proof of principle studies for future therapeutic approaches in neurodegenerative research. This mini review will specifically focus on utilising Drosophila as an in vivo model of amyloid toxicity in AD.