Abstract
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.
Original language | English |
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Pages (from-to) | 4769-4782 |
Number of pages | 14 |
Journal | Cerebral cortex (New York, N.Y. : 1991) |
Volume | 27 |
Issue number | 10 |
DOIs | |
Publication status | Published - 1 Oct 2016 |
Keywords
- Alzheimer Disease/physiopathology
- Amyloid beta-Peptides/metabolism
- Cell Death/drug effects
- Cognition/drug effects
- Hippocampus/metabolism
- Humans
- Leptin/metabolism
- Memory/drug effects
- Neuronal Plasticity/physiology
- Neurons/metabolism
- Peptide Fragments/metabolism
- Synapses/drug effects