Characterisation of leptin mimetic agents as therapeutic targets in Alzheimer's disease

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder which is characterised by amyloid β (Aβ) plaques formation and neurofibrillary tangles. Aβ accumulation leads to hippocampal synaptic disruption and neuronal cell death. The endocrine hormone leptin, regulates food intake and body weight. However, leptin also has an important role in modulating excitatory synaptic transmission and synaptic plasticity at hippocampal synapses. Furthermore, recent studies have shown that leptin function is impaired in models of AD. Indeed, circulating levels of leptin are much lower in AD patients and rodent. Leptin also has the ability to prevent the detrimental effects of Aβ on hippocampal synaptic function and cell survival. Therefore, leptin may be an important therapeutic target in the treatment of AD. However, as leptin has many different roles in the periphery and CNS, developing smaller leptin-like molecules with specific actions may be a more ideal therapeutic approach.<br/><br/>Recent studies indicate that several fragments of the leptin protein are bio-active in terms of regulating energy homeostasis. However, it is unclear if these leptin fragments are active in the CNS and mirror the cognitive enhancing and neuroprotective actions of the whole leptin molecule. Thus, in this study, the effects of the reported bio-active leptin fragments, leptin (116-130) and leptin (22-56) on excitatory synaptic transmission and synaptic plasticity at hippocampal CA1 synapses were examined using standard extracellular field recordings. The effects of the two leptin fragments on AMPA receptor trafficking was also examined using immunocytochemical approaches. In addition, the ability of the bio-active fragments to protect against Aβ-induced synaptic toxicity was explored.<br/><br/>The results from this study reveal that the potential cognitive enhancing effects of leptin on excitatory synaptic transmission and AMPA receptor trafficking were mirrored by leptin (116-130). In contrast, acute application of leptin (22-56) had no effect on hippocampal excitatory synaptic function or AMPA receptor trafficking. Moreover, in a manner similar to leptin, leptin (116-130) prevented hippocampal synaptic impairment and AMPA receptor internalisation induced by Aβ. In contrast, leptin (22-56) displayed no neuroprotective effects against Aβ. As leptin (116-130) was identified as the bio-active fragment, smaller leptin fragments consisting of six amino acids were then generated in order to identify the key amino acids that make leptin (116-130) a bio-active fragment. Application of the first four hexamer fragments (116-121; 117-122; 118-123; 120-125) mirrored the ability of leptin (116-130) to facilitate LTP. In addition these fragments also mirrored leptin (116-130) effects on GluA1 surface expression. In contrast, the last four hexamer fragments (121-126; 123-128; 124-129; 125-130) showed no effects on hippocampal LTP or GluA1 surface expression.<br/><br/>Finally, the active site of the leptin molecule lies between amino acids Ser-116 and Thr-122 which is in agreement with previous studies looking at the effects of bio-active fragments on food intake and body weight. However, our data suggests that the active site is extended beyond Ser-116, Cys-117, Ser-118, Leu-119, Pro-120, Gln-121 and Thr-122 as leptin (120-125) was also active in our assays. Therefore, application of leptin mimetics could be a more suitable and effective therapeutic target for clinical management of AD.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2016

Author dc:creator

• Malekizadeh, Yasaman

Advisor dc:contributor.advisor

• Harvey, Jenni

• Leptin
• Bio-active leptin fragments
• Synaptic plasticity
• Alzheimer's disease

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/8fec422e-d587-458c-b14e-420e9ce67584

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/8fec422e-d587-458c-b14e-420e9ce67584