Leptin regulates amyloid β production via the γ-secretase complex

Abstract

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, affecting an estimated 5.3million people in the United States. While many factors likely contribute to AD progression, it is widely accepted that AD is driven by the accumulation of β-amyloid (Aβ), a small, fibrillogenic peptide generated by the sequential proteolysis of the amyloid precursor protein by the β- and γ-secretases. Though the underlying causes of Aβ accumulation in sporadic AD are myriad, it is clear that lifestyle and overall health play a significant role. The adipocyte-derived hormone leptin has varied systemic affects, including neuropeptide release and neuroprotection. A recent study by Lieb et al. (2009) showed that individuals with low plasma leptin levels are at greater risk of developing AD, through unknown mechanisms. In this report, we show that plasma leptin is a strong negative predictor of Aβ levels in the mouse brain, supporting a protective role for the hormone in AD onset. We also show that the inhibition of Aβ accumulation is due to the downregulation of transcription of the γ-secretase components. On the other hand, β-secretase expression is either unchanged (BACE1) or increased (BACE2). Finally, we show that only presenilin 1 (PS1) is negatively correlated with plasma leptin at the protein level (p<0.0001). These data are intriguing and may highlight a role for leptin in regulating the onset of amyloid pathology and AD.

Figure 1. Plasma Leptin Negatively Correlates with Brain Aβ

There was a strong negative correlation between plasma leptin and brain Aβ in young (2–3 month-old) APP^ΔNLh x PS1^P264L knock-in mice (N=105; p<0.0001).

Figure 2. Leptin Treatment Inhibits Aβ Production in Cell Culture

Leptin reduced the Aβ concentration in conditioned media from APP^ΔNLh-overexpressing H4 neuroglioma cells after 24 hours of treatment (A; * = p<0.05), concomitant with accumulation of APP C-terminal fragments (CTFα and β: B), indicative of reduced γ-secretase activity. Two independent experiments were performed. A is an average of the two experiments, while B is a representative immunoblot of the results.

Figure 3. Leptin Treatment Reduces mRNA Levels of γ-Secretase Components in Cell Culture

mRNA expression of the γ-secretase components PS1, PEN2, nicastrin, and APH1 were decreased after leptin treatment in wild-type neuronal tissue culture cells. On the contrary, there was an overall increase in the expression of BACE2 (p=0.014), one of the β-secretase enzymes. There was no change in PS2 or BACE1 mRNA expression (p>0.12). The data are an average of 2–3 independent experiments.

Figure 4. Plasma Leptin Negatively Correlates with PS1 Expression in Brain

Plasma leptin was strongly and negatively correlated with brain PS1 protein levels (A: N=65; p<0.0001), but not other γ-secretase components (not shown: N=65; PEN2, p<0.727; APH1A, p<0.591). The amount of PS1 protein was positively correlated with brain Aβ (B: N=65; p<0.004). Brain nicastrin (C) displayed a shift to a smaller molecular weight with increasing plasma leptin concentrations (D: N=16; p=0.03), indicating accumulation of an immature form of the protein. Similarly, leptin treatment of H4 cells led to accumulation of the immature form of nicastrin (E), though the change was not significant (F: N=1-; p=0.31).