A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models

Abstract

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.

Author summary

Dementias are caused by the accumulation of toxic proteins in the brain of patients. These proteins form dense clumps either within or outside brain cells, leading to the death of these cells, which leads to the symptoms of dementia. Different types of dementias are caused by different types of proteins, however when patients go to the clinic, it’s often quite difficult to say which type of dementia the patient is presenting with. A therapeutic approach valid across different dementias would therefore be very useful, as it would not be reliant on accurate diagnosis. We have discovered that we can raise the influx of pyruvate into brain cells by increasing the amount of a transporter protein called bumpel. This leads to a drop in the levels of a number of toxic proteins, associated both with Frontotemporal Dementia and Alzheimer’s disease. We also find that decreasing these proteins leads to an improvement of the lifespan and behaviour of fly models of disease.