University of Dundee

MRC DTP 4 Year PhD Programme: Investigations into the neuroprotective actions of leptin in cellular models of tauopathy.

Nerve cells in the brain are interconnected within complex networks and synaptic communication within these brain networks determines how we think and behave. 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. Indeed, metabolic imbalance is an important contributory factor in AD and recent evidence has linked the hormone leptin to an increased incidence of AD. Thus leptin-based therapies may be beneficial in AD. Our recent studies support this possibility as we have identified a potential cognitive enhancing role for leptin as it regulates diverse aspects of synaptic function including glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity (1). Furthermore, treatment with leptin prevents hippocampal synaptic disruption and neuronal death in cellular models of AD (2; 3). However our understanding of the neuroprotective actions of leptin in human AD pathology is limited.

In order to closely mirror human pathophysiology, we propose, (in collaboration with Dr Marios Stavridis, Dundee), to use human induced pluripotent stem cell (iPSC) technologies together with directed differentiation to generate human iPSC-derived neurons with classical features of AD pathophysiology. We will use iPS cells derived from control and AD patients with specific identified tau mutations and differentiate these to glutamatergic neurons using established protocols (4). Once generated, we propose to compare and contrast the synaptic and physiological features of iPSC-derived neurons from control and AD patients. Using state-of-the-art molecular, imaging and electrophysiology approaches, we will then examine the impact of leptin and leptin-derived fragments (3) in preventing synaptic dysfunction and neuronal cell death in iPSC-derived neurons. This study will provide valuable information on why dementia occurs and also potential novel therapeutic targets.

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. Neurobiology of 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.
  4. Zeng H, Guo M, Martins-Taylor K, et al. (2010). Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells. PLoS One 5(7):e11853

Eligibility