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

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.