A leptin fragment mirrors the cognitive enhancing and neuroprotective actions of leptin
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A key pathology of Alzheimer’s disease (AD) is amyloid β (Aβ) accumulation which 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.
Malekizadeh , Y , Holiday , A R , Redfearn , D , Ainge , J A , Doherty , G H & Harvey , J 2016 , ' A leptin fragment mirrors the cognitive enhancing and neuroprotective actions of leptin ' Cerebral Cortex , vol In press . DOI: 10.1093/cercor/bhw272
© The Author 2016. Published by Oxford University Press. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://dx.doi.org/10.1093/cercor/bhw272
J.H. is funded by The Anonymous Trust and Cunningham Trust. GD is funded by ARUK, DR received a University of St Andrews Research Internship. JAA is funded by the Carnegie Trust.
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