Leptin: A Novel Therapeutic Strategy for Alzheimer's Disease

Abstract

Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. One activity of leptin is the control of AMPdependent kinase (AMPK). In addition to maintaining lipid levels, AMPK regulates glycogen synthase kinase-3, which modulates tau phosphorylation. Leptin has been shown to reduce the amount of extracellular amyloid-β, both in cell culture and animal models of AD, as well as reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models of AD. In humans, weight loss often precedes the onset of dementia in AD and the level of circulating leptin is inversely proportional to the severity of dementia among AD patients. It is speculated that a deficiency in leptin levels or function may contribute to systemic and central nervous system abnormalities leading to AD, suggesting that a leptin replacement therapy may be beneficial for AD. This may be an attractive alternative to the drugs that are currently under development.

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

“…3). In concert with other adipocytokines, such as leptin75, a complicated mode of APN may act as a driving force in AD pathogenesis.…”

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

“…A recent case-control study has measured the serum levels of adiponectin and leptin in the same cohorts of AD and confirmed a raised level of adiponectin and a lower leptin level in serum of AD subjects which are in good correlation with the severity of the disease as measured by MMSE scores [49]. Extensive experimental studies in cell lines and AD transgenic mice have indicated that leptin can affect APP-Aβ trafficking, Aβ accumulation and clearance, βsecretase expression as also phosphorylation of tau protein [139,140,147].…”

Clinicotherapeutic Potential of Leptin in Alzheimer’s Disease and Parkinson’s Disease

“…Improved memory following leptin administration has also been found in SAMP-8 mice, an accelerated senescence rodent model that develops amyloid plaques [37]. Chronic leptin administration to the APPoverexpressing mouse, Tg2576, by implanted miniosmotic pumps reduced brain amyloid levels significantly [44,47]. In a recent study by Doherty et al, it has been shown that leptin reverses the A inhibition of hippocampal LTP, reduces Ainduced facilitation of long-term depression (LTD) by PI3 kinase pathway, protects against A -induced internalization of glutamate receptor 1 subunit (GluR1) by PI3 kinasedependent mechanism thereby preventing removal ofamino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors from the synapses in hippocampal neurons, protects cortical neuronal death against A -mediated toxicity by STAT3-mediated pathway, and reduces A -induced expression of synaptic protein endophilin 1 and phosphorylated tau in cortical neurons both in vitro and in vivo [50].…”

“…Leptin prevents neuronal death by reducing A levels both in vitro and in vivo, as well as by reducing tau hyperphosphorylation [40,41]. The neuroprotective role of leptin has been extensively studied in both in vitro and in vivo models of neurodegeneration [42][43][44]. In vitro model of PD using cultured dopaminergic cells exposed to the neuronal toxin 6-hydroxydopamine (6-OHDA) has shown protection from death by leptin [39,42].…”