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. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Figure 1

Leptin can modulate AMPK activity following binding to the leptin receptor. The precise mechanism is currently unknown but there is some evidence that this may involve STAT3. There is considerable information regarding events downstream of AMPK leading to tau phosphorylation, which involves modulation of GSK-3β via Akt. In contrast, the cascade from AMPK to Aβ homeostasis is less defined. Activated AMPK may turn-off the transcriptional factors SREBP1,2, known to regulate lipid metabolism (fatty acid synthase, palmitoyl transferase etc.), previously shown to be downregulated by leptin [40]. There is some evidence that insulin is also capable of modulating AMPK. In addition to AMPK, insulin and leptin may share another common target, PI3K, which also regulates GSK-3β through Akt. Activation of Akt by AMPK leads to the phosphorylation of GSK-3β at Ser-9 which deactivates it. GSK-3β is the major kinase for tau. Based exclusively on our studies, AMPK is emerging as a central modulator of major pathological pathways in AD. We propose that leptin deficiency in AD contributes to the downregulation of the AMPK system. This in turn causes increases in Aβ and phosphorylated tau. A lower AMPK activity may also be associated with a general low metabolic activity within neurons, an overall neuronal “fatigue”. Infusing leptin in the AD brain may improve the outlook, boosting metabolic pathways and reducing Aβ and phospho-tau. A better understanding of the AMPK system as it relates to AD pathways can provide more targets for future drug discovery efforts.