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.
Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, DundeeDD1 9SY, UK.
Yasaman
Y
Malekizadeh
School of Psychology and Neuroscience, St Mary's Quad, University of St Andrews, St Andrews, FifeKY16 9TS, UK.
Alison
A
Holiday
School of Psychology and Neuroscience, St Mary's Quad, University of St Andrews, St Andrews, FifeKY16 9TS, UK.
Devon
D
Redfearn
School of Psychology and Neuroscience, St Mary's Quad, University of St Andrews, St Andrews, FifeKY16 9TS, UK.
James A
JA
Ainge
School of Psychology and Neuroscience, St Mary's Quad, University of St Andrews, St Andrews, FifeKY16 9TS, UK.
Gayle
G
Doherty
Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, DundeeDD1 9SY, UK.
Jenni
J
Harvey
D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D020738:Leptin; D010446:Peptide Fragments; C410793:leptin (116-130); C487163:leptin 22-56
AMPA receptor trafficking; Alzheimer's disease; amyloid beta; episodic memory; hippocampus; synaptic plasticity