There is overwhelming evidence underlying the importance of metabolic pathways in the course of AD. First, from several genetic studies, it has been established that carriers of the ApoE4 allele are an order of magnitude more likely to get AD [69
]. Second, the effect of diet and nutrition on the prevalence of AD has been documented [70
] and weight loss is frequently observed in AD patients prior to the onset of dementia [73
]. Further, central obesity is associated with an increased risk for dementia [37
]. Third, in cell culture and animal models it has been demonstrated that lipids play an important role in amyloidogenic pathways [75
]. Fourth, the majority of AD patients have some form of insulin resistance or hyperinsulinemia or type II diabetes [76
Thus, it is not surprising that modulators of cholesterol (i.e., statins) and glucose (i.e., rosiglidazone) [77
] are being developed as potential AD therapeutics. In fact, cholesterol-reducing therapies such as statins have been shown to reduce Aβ deposition both in vivo
and in vitro
]. These are in agreement with epidemiological studies documenting a decreased prevalence of AD with the use of statins [79
]. Interestingly, the rosiglidazone studies have revealed an important association between the drug's efficacy as a cognitive enhancer in AD patients and their ApoE genotype [80
]. As the mechanism of action for leptin appears to be substantially unique compared to any of the approved drugs and any of those under development, increasing the availability of leptin in the CNS holds promise as an AD therapy ().
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 (more ...)
AMPK is an important enzyme for regulation of cellular metabolic activity. AMPK acts as a master switch regulating several intracellular systems including the cellular uptake of glucose, the β-oxidation of fatty acids and the biogenesis of glucose transporter 4 (GLUT4) and mitochondria [81
]. AMPK may be important for CNS development as supported by the phenotype of the Drosophila mutant löchrig which has a defective AMPK [82
] and abnormal cholesterol levels that results in extensive neurodegeneration.
It has been shown that leptin directly activates AMPK [83
] and our laboratory has demonstrated that the ability of leptin to modulate both tau phosphorylation and Aβ production are mediated through AMPK [14
] (Greco et al., unpublished results). By utilizing a panel of known inhibitors and activators of candidate leptin signaling molecules, in addition to the employment of recombinant expression and siRNA technology, it became apparent that a number of targets upstream, but not downstream, of AMPK could simultaneously modulate Aβ and tau phosphorylation.
Thus based on the available data, perhaps in AD, select neuronal populations may have a deficient/defective AMPK system for one or more of the following reasons: low leptin/insulin levels, low leptin/insulin sensitivity, hyperactive GSK-3β, abnormal cholesterol and fatty acid membrane composition, and low glucose uptake. This can then lead to changes in synaptic properties, an increase in amyloid deposition, an increase in tau phosphorylation, and finally death.
Other pharmacological agents known to modulate AMPK, such as metformin, an insulin-sensitizing antidiabetic drug [28
], and 5-aminoimidazole-4-carboxamide ribonucleoside, an adenosine analogue (AICAR) could in principal at least partially replace the biological activity of leptin in pathways leading to AD pathology. To this end, rosiglitazone, a thioglitazone, and PPARγ agonist (see above), may also act through AMPK [84