Leptin-based hexamers facilitate memory and prevent amyloid-driven AMPA receptor internalisation and neuronal degeneration

Key pathological features of Alzheimer's disease (AD) include build-up of amyloid beta (A beta), which promotes synaptic abnormalities and ultimately leads to neuronal cell death. Metabolic dysfunction is known to influence the risk of developing AD. Impairments in the leptin system have been detected in AD patients, which has fuelled interest in targeting this system to treat AD. Increasing evidence supports pro-cognitive and neuroprotective actions of leptin and these beneficial effects of leptin are mirrored by a bioactive leptin fragment (leptin(116-130)). Here we extend these studies to examine the potential cognitive enhancing and neuroprotective actions of 8 six-amino acid peptides (hexamers) derived from leptin(116-130). In this study, we show that four of the hexamers (leptin(116-121, 117-122, 118-123) and (120-125)) replicate the ability of leptin to promote alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and facilitate hippocampal synaptic plasticity. Moreover, the pro-cognitive effects of the hexamers were verified in behavioural studies, with the administration of leptin(117-122) enhancing performance in episodic memory tasks. The bioactive hexamers replicated the neuroprotective actions of leptin by preventing the acute hippocampal synapto-toxic effects of A beta, and the chronic effects of A beta on neuronal cell viability, A beta seeding and tau phosphorylation. These findings provide further evidence to support leptin and leptin-derived peptides as potential therapeutics for AD.

Automated summary

Key pathological features of Alzheimer's disease (AD) include the accumulation of amyloid beta (Aβ) and metabolic dysfunction. Impairments in the leptin system have been detected in AD patients, sparking interest in targeting this system for AD treatment. This study examines the cognitive enhancing and neuroprotective actions of six-amino acid peptides derived from leptin(116-130) in promoting synaptic plasticity and improving memory tasks. The hexamers replicate the effects of leptin in promoting AMPA receptor trafficking and preventing toxic effects of Aβ on hippocampal synapses and neuronal viability. These findings further support leptin and leptin-derived peptides as potential therapeutics for AD.