Evaluating the therapeutic potential of leptin-based hexamers in neurodegenerative disease

Translation of basic research into Alzheimer’s disease (AD) therapies is hindered by our inability to turn promising lab results into drugs that can be taken by patients. One way of addressing this, is to use compounds that we know are safe for human use, in pre-clinical studies examining the network properties that degrade in AD. Our previous work has identified that fragments of the metabolic hormone, leptin, prevent AD-related neurodegeneration and improve the type of memory that is first impaired in AD. In this project, we will extend this work to examine how leptin-based fragments affect a key pathological trait of AD: build-up of neurofibrillary tangles comprising hyper-phosphorylated tau. 

Tau modification and its accumulation in neurons strongly correlate with cognitive deficits and synaptic deficits in early AD. In healthy neurons, tau is concentrated in axons, but phosphorylation of tau in AD, targets it to synapses where it causes synaptic dysfunction. Consequently, limiting tau effects on synaptic function may prevent the synaptic abnormalities underlying AD-related cognitive deficits. However, our understanding of how tau impairs synaptic function, and how tau-related synaptic dysfunction can be targeted therapeutically is limited. Here, we propose to assess the neuroprotective actions of leptin-based fragments in tau models of dementia. This will include using a combination of electrophysiology, and confocal imaging techniques to assess beneficial effects in tau models of synaptic pathology. A range of behavioural tasks will be used to determine effects on hippocampus-dependent memory processes, whereas the synaptic expression of leptin receptors and associated targets will be determined in rodent and human tissue using state-of the art array tomography.

This study will facilitate the advancement of leptin-based drugs as a potential treatment for AD.

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