Increased expression of Alzheimer's disease related genes in obesity
Mohamed, Islam Nabil Mohamed Badr
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Many epidemiological studies have demonstrated that obesity is associated with an increased incidence and prevalence of Alzheimer’s disease (AD) which is characterized by plaques of β-amyloid (Aβ) peptides formed from its precursor: Aβ precursor protein (APP) and neurofibrillary tangles made up of hyperphosphorylated TAU protein. We have now investigated the expression of APP and TAU as well as the proteins/enzymes involved in the formation and destruction of these proteins in the adipose tissue of obese subjects. Obese subjects (n=24, Age=36.8 ±1.157, Males = 8, BMI = 33.8 ±0.579) had higher mRNA expression levels of the two key proteins, APP by 22.4% ( P =0.018) and TAU by 34% ( P =0.023) when compared to lean control subjects (n=19, Age = 33.2 ±1.577, Males = 8, BMI = 22.5 ±0.446). The mRNA expression of Aβ converting enzyme (BACE1), the main enzyme involved in the formation of Aβ peptides was increased as was the mRNA expression of the enzymes involved in Aβ peptides preclusion and degradation: ADAM-9, ADAM 17 and IDE by 22.3% ( P =0.016), 53.8% ( P =<0.001), 32.6% ( P = 0.002) and 19% ( P =0.024) respectively in the obese group. In addition, there was an increase in the mRNA expression of the major pro-inflammatory mediators: MIF by 26.8% ( P =0.007), MCP-1 by 195% ( P =0.004) and MMP-9 by 79.6% ( P =0.037) in the obese group. BMI correlated significantly with BACE1, ADAM 9, ADAM 17, IDE, TAU, GSK3β, MIF and MCP-1 mRNA expression. MIF and MCP-1 mRNA expression in turn correlated significantly with that of BACE1, ADAM 9, ADAM 17 and IDE. Plasma Aβ1-42 and Aβ1-40 peptide levels were lower in the obese group by 9.2% ( P =0.033) and 15.8% ( P =0.008) respectively and there was no significant difference in plasma Aβ1-42/Aβ1-40 ratio between groups. The state of obesity is, therefore, associated with an increased gene expression of APP, TAU and BACE1 with a concomitant increase in that of Aβ precluding and degrading enzymes in parallel with an increase in pro-inflammatory gene expression. Whether this up-regulation of both the synthetic and precluding/degrading pathways in adipose tissue reflects a similar activity in the brain and whether this increase is dependent upon inflammatory mechanisms needs to be investigated in future.