Alzheimer’s disease has a devastating impact on aging individuals, causing memory loss and confusion, and progresses to include symptoms such as a loss of ability to communicate and seizures (1). As populations continue to live longer, understanding why AD happens is becoming more imperative. There’s currently no treatment to slow or prevent the disease process, while 5.1 million people aged 65+ in the U.S. alone are suffering from AD, and many more worldwide. Reflecting the urgency to discover an effective mechanism to stop AD, there has been a 25% increase in funding from 2011 to 2014 for Alzheimer’s research by the U.S. National Institutes of Health (2). Research has discovered many new facets of the disease, including discovering the roles of microRNAs (see the slide deck), but there is still a lot to learn.
Glucose metabolism, oxidative stress and AD
Impairment in glucose metabolism and insulin resistance has been a hot topic in AD research in recent years, and for good reason. Type II diabetes is a known risk factor for AD – in a recent review, Saedi and colleagues noted a 45–90% association of diabetes with AD, and also that even pre-diabetes, regardless of progression, confers a higher risk of AD. Brain atrophy has also been noted in diabetic patients (3).
The link between Type II diabetes and AD may lie in the effects of glucose metabolism dysregulation and oxidative stress. Verdile et al. note that 3 aspects of insulin resistance present in Type II diabetes, hyperglycemia, hyperlipidemia and hyperinsulinemia, are all known to boost accumulation of amyloid beta, one of the hallmarks of Alzheimer’s disease, and that the inverse, amyloid beta promoting insulin resistance, has also been demonstrated in the liver. Even independent of insulin resistance, studies have shown that excess glucose leads to persistently higher amyloid beta in interstitial fluid as well as lowered neuronal activity and hippocampal metabolism, suggesting that these damaging processes may begin even prior to full-blown T2D (4).
Verdile et al. also discuss how chronic reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced as a result of overnutrition, partially due to reduced generation of the free radical-scavenging glutathione (GSH) by a variety of mechanisms. The reduced ability to scavenge free radicals, they note, could lead to damage of both beta-cells and neurons, driving both T2D and AD (4).
New findings: 8-oxoG and AD, and how a glucose transporter influences memory
Studies continue to shed light on the link between glucose metabolism, oxidative stress and Alzheimer’s disease. 8-oxoguanine (8-oxoG), a DNA lesion resulting from oxidative damage, is prevalent in AD brains, as well as other neurodegenerative disorders like Parkinson’s and Huntington’s disease (5). Recently, Leon et al. generated a double knockout mouse lacking both OGG1 and MTH1, two genes involved in minimizing the accumulation of 8-oxoG in mtDNA. They found that the absence of these genes led to higher 8-oxoG in mtDNA both in the presence of antioxidants (although only slightly) and in the absence of antioxidants (more pronounced), as well as diminished neurite extension and arborisation, indicating defects in neuritogenesis (5). Another study, by Sliwinska et al., examined the potential of 8-oxoG and OGG1 as biomarkers for AD, confirming that 8-oxoG was higher in DNA from peripheral tissues in individuals with AD vs controls, and that serum levels of OGG1 were lower in AD individuals compared to healthy controls (6).
Another recent report in the Journal of Neuroscience, by Pearson-Leary and McNay, took the novel step of studying how changes to GluT4, an insulin-regulated glucose transporter, in hippocampal neurons affected memory formation. They found that GluT4 is important for memory acquisition, but that intriguingly, its long-term inhibition had varying impacts: short-term and working memory improved, whereas long-term memory was negatively affected (7).
Oxidative stress and glucose metabolism gene expression profiling
It’s clear that Alzheimer’s disease is associated with oxidative stress and glucose metabolism impairment, so could studying these pathways more closely yield important information about disease progression? Targeted RNA sequencing is an emerging technology for getting the gene expression accuracy of next-generation sequencing without the overwhelming amount of data involved in sequencing the whole transcriptome. The QIAseq Targeted RNA Panels for oxidative stress, glucose metabolism and Alzheimer’s disease enable fast, accurate interrogation of these pathways using Unique Molecular Indices to eliminate PCR bias.
- 1. About Alzheimer’s Disease: Symptoms. https://www.nia.nih.gov/alzheimers/topics/symptoms
- 2. 2014-2015 Alzheimer’s Disease Progress Report: Advancing Research Toward a Cure. https://www.nia.nih.gov/alzheimers/publication/2014-2015-alzheimers-disease-progress-report/introduction
- 3. Saedi, E., Gheini, M.R., Faiz, F. and Arami, M.A. (2016) Diabetes mellitus and cognitive impairments. World J. Diabetes 7, 412–422. Link
- 4. Verdile, G. et al. (2015) Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity and Alzheimer’s Disease. Mediators Inflamm. 2015, 105828. Link
- 5. Leon, J., Sakumi, K., Castillo, E., Sheng, Z., Oka, S. and Nakabeppu, Y. (2016) 8-oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions. Sci. Rep. 6, 22086. Link
- 6. Sliwinska, A. et al. (2016) The levels of 7,8-dihydrodeoxyguanosine (8-oxoG) and 8-oxoguanine DNA glycosylase 1 (OGG1) – a potential diagnostic biomarkers of Alzheimer’s disease. J. Neurol Sci. 368,155–9. Link
- 7. Pearson-Leary, J. and McNay, E.C. (2016) Novel roles for the insulin-regulated glucose transporter-4 in hippocampally dependent memory. J. Neurosci. 36, 11851–11864. Link