Neurodegenerative diseases such as Alzheimer’s not only destroys the quality of life of patients, but also of their friends and families. Managing the psychological and cognitive effects of the brain lesions associated with Alzheimer’s disease is a devastating endeavor. Finding a way to thwart the progress or completely eradicate from the brain such a disease would be an incredible feat. We BCM441 students recently discussed the prevalence of Alzheimer’s disease in diabetic patients that have elevated systemic levels of glucose. In this Nature article, though, entitled “Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia”, the researchers focus on patients without type 2 diabetes or impaired glucose tolerance and find that there are localized, significantly altered levels of multiple metabolites in the brains of Alzheimer’s disease (AD) patients (Xu et al. 2016).
The authors of this paper recognize that many different factors contribute to the onset of AD, but they aim to center their study on the metabolic aspect of the disease. These researchers used mass spectrometry to look at metabolite levels in seven different regions of the brains of nine AD patients and nine controls (post-mortem). They also studied plasma-glucose and plasma-copper (will be explained) levels in ante-mortem human brains. Their findings were very interesting. In the nine AD patients, glucose, fructose, and sorbitol levels were significantly elevated. However, the brain tissue in these patients was deficient in copper. They found that these metabolite levels in the ante-mortem brain tissue, though, were unaltered. In the nine AD patients, there was variation in the glucose elevation in different brain regions, and furthermore, they found that there were much higher levels of glucose in brain tissue that was more severely damaged. Levels of sorbitol and fructose varied insignificantly among different brain regions. Copper levels in the AD brain seemed to be inversely proportional to the levels of glucose. Hence, in tissues with very high glucose levels, there would be corresponding low levels of copper (Xu et al. 2016).
The increased levels of glucose, fructose, and sorbitol and decreased levels of copper in the brain tissue of AD patients were very significant and led to some interesting speculation and ideas for further discussion. What is amazing about these results is that we know that diabetics are often victims of AD, and the obvious similarity between diabetics and the patients in this study are that they have elevated glucose levels. It just happens to be systemic in diabetics and due to insulin resistance. So, we can see that these elevated metabolite levels have something to do with disease mechanism. Now we can address what the authors were thinking about these results.
Their first thought dealt with the fact that there is known decreased activity of GLUT1 transporters in AD, which is consistent with the fact that GLUT1 is the main glucose transporter in the blood brain barrier. The problem with this idea is that there are elevated glucose levels in the cell. Thus, the authors concluded that the high intracellular glucose levels (causing an unnaturally steep gradient) likely downregulates the expression of GLUT1, lowering its activity (Xu et al. 2016). So, why are these glucose levels so high? Well, it is also true that in AD, glycolysis and the TCA cycle are impaired. The authors cite that pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and cytochrome c oxidase/complex IV (mitochondrial enzymes) are impaired in AD (Xu et al. 2016). If the enzymes that catabolize glucose are not working, we probably have elucidated the mystery of the elevated glucose levels. This also seems to explain the alternative route for glucose down the polyol pathway, hence the elevated fructose and sorbitol levels.
Now that we have established possible causes for glucose elevation, how does this relate to neurodegeneration? First, advanced glycation end products (AGEs) must be discussed. This phenomenon is very prevalent in diabetes because of increased glucose levels. High glucose (and fructose) results in the formation of AGEs because of the aldehyde (and ketone), which can be attacked by reactive functional groups on macromolecules in the cell (Gkogkolou and Böhm 2012). It is known that AD brains contain N-epsilon-carboxymethyllysine (CML) which is an advanced glycation end product that coordinates divalent copper (decrease in copper levels is indeed VERY relevant) (Xu et al. 2016). CML essentially steals the copper away from enzymes that need it like cytochrome oxidase (complex IV in the electron transport chain!) – super important for cellular fuel – and superoxide dismutase, which helps to fight against oxidative damage (crucial for cell health). Increased glucose concentrations “drive CML-modification of collagen, which inhibits cell-copper uptake by suppressing cell-membrane copper transport via copper transporter 1” (Xu et al. 2016). If cytochrome c oxidase is deficient in copper, fuel production in cells can be severely impaired and cell death can ensue. The authors believe the big copper ordeal is a good place for a therapeutic target in AD patients (Xu et al. 2016).
In summary, this high impact work shows the science community that patients with AD exhibit localized, elevated brain glucose levels and there are a few mechanisms by which this can lead to neurodegeneration and the debilitating AD symptoms that follow. Drug therapies that hit these spots addressed in this study must be seriously considered in order to help better the lives of those unfortunate enough to encounter such a wicked disease.
Figure 1. This picture shows the formation of CML which, as described by the study, has heavy implications in the pathogenesis of Alzheimer’s Disease. Interestingly enough, the formation of this advanced glycation end product (given high glucose concentrations) does proceed through a Schiff base intermediate.
Gkogkolou, Paraskevi, and Markus Böhm. 2012. “Advanced Glycation End Products.” Dermato-Endocrinology 4 (3): 259–70. doi:10.4161/derm.22028.
Xu, Jingshu, Paul Begley, Stephanie J. Church, Stefano Patassini, Selina McHarg, Nina Kureishy, Katherine A. Hollywood, et al. 2016. “Elevation of Brain Glucose and Polyol-Pathway Intermediates with Accompanying Brain-Copper Deficiency in Patients with Alzheimer’s Disease: Metabolic Basis for Dementia.” Scientific Reports 6 (June): 27524. doi:10.1038/srep27524.