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.