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Cereb Cortex. 2017 Oct 1;27(10):4769-4782. doi: 10.1093/cercor/bhw272.

A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin.

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Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, DundeeDD1 9SY, UK.
School of Psychology and Neuroscience, St Mary's Quad, University of St Andrews, St Andrews, FifeKY16 9TS, UK.


A key pathology of Alzheimer's disease (AD) is amyloid β (Aβ) accumulation that triggers synaptic impairments and neuronal death. Metabolic disruption is common in AD and recent evidence implicates impaired leptin function in AD. Thus the leptin system may be a novel therapeutic target in AD. Indeed, leptin has cognitive enhancing properties and it prevents the aberrant effects of Aβ on hippocampal synaptic function and neuronal viability. However, as leptin is a large peptide, development of smaller leptin-mimetics may be the best therapeutic approach. Thus, we have examined the cognitive enhancing and neuroprotective properties of known bioactive leptin fragments. Here we show that the leptin (116-130) fragment, but not leptin (22-56), mirrored the ability of leptin to promote AMPA receptor trafficking to synapses and facilitate activity-dependent hippocampal synaptic plasticity. Administration of leptin (116-130) also mirrored the cognitive enhancing effects of leptin as it enhanced performance in episodic-like memory tests. Moreover, leptin (116-130) prevented hippocampal synaptic disruption and neuronal cell death in models of amyloid toxicity. These findings establish further the importance of the leptin system as a therapeutic target in AD.


AMPA receptor trafficking; Alzheimer's disease; amyloid beta; episodic memory; hippocampus; synaptic plasticity

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