Investigations into the neuroprotective actions of leptin and leptin-based mimetics in models of tauopathy.

In neurodegenerative disorders like Alzheimer’s disease (AD), synaptic communication within brain networks are impaired leading to significant memory deficits and dementia. Clinical studies indicate that diet and lifestyle are key risk factors for AD, with metabolic imbalance identified as an important contributory factor. Recent studies have linked the metabolic hormone leptin to an increased incidence of AD, which has fuelled the possibility that leptin-based therapies may be beneficial in AD. Indeed, our recent studies support this as we have identified not only a cognitive enhancing role for leptin (1), but treatment with leptin prevents hippocampal synaptic disruption and neuronal death in amyloid-based models of AD (2). Moreover, we have recently identified that the whole leptin molecule is not required for bioactivity, as a leptin fragment (leptin amino acids 116-130) mirrors the cognitive enhancing and neuroprotective actions of leptin. However our understanding of the neuroprotective actions of leptin in human AD pathology and in particular tau pathology is limited. Here we aim to use a range of model systems, including human induced pluripotent stem cell (iPSC) technologies, to mirror tau pathophysiology that occurs in human cases of AD, with a view to increasing our understanding of the neuroprotective and potential therapeutic actions of leptin and leptin fragments.

References.

1. Irving AJ, Harvey J. (2013). Leptin regulation of hippocampal synaptic function in health and disease. Phil. Trans. B. 369: 20130155
2. Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ, Harvey J (2012). Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β. Neurobiol. Aging 34(1):226-37.
3. Malekizadeh Y, Holiday A, Redfearn D, Ainge JA, Doherty G, Harvey J. (2017). A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin. Cereb Cortex. 27(10):4769-4782



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