Filling in the Missing Pieces: Study Finds Causative Role for Uncontrolled Diabetes in Alzheimer’s Disease

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Diabetes mellitus is one of the most common chronic diseases, globally. The prevalence has risen from 4.7% of adults over 18 years of age in 1980 to 8.5% in 20141. Plagued by treatment non-compliance, it is estimated that approximately 50% of Type 2 Diabetics fail to achieve adequate glycemic control2. The positive association between diabetes and Alzheimer’s disease is well known. A large population-based study in Rotterdam has suggested that diabetes can almost double the risk of developing Alzheimer’s disease and vascular dementia3. The link, however between the metabolic disorder and the devastating neurological disease has remained the object of speculation.

Alzheimer’s disease (AD) is characterized by two types of brain lesions – extracellular β-amyloid (Aβ) accumulation in amyloid plaques and intracellular aggregation of hyperphosphorylated tau into neurofibrillary tangles4. A study detailed in Nature Scientific Reports, investigated the effect of high glucose on β-site amyloid precursor protein cleaving enzyme 1 (BACE1) expression and amyloidogenesis in vivo. BACE1 is the enzyme responsible for initiating β-amyloid (Aβ) generation from amyloid precursor protein (APP). Amyloid deposition begins10-20 years before Alzheimer’s dementia onset, suggesting an early role in pathogenesis for Aβ accumulation; making BACE1 a desirable target of study5.

In their study, Dr. Ho Jae Han and his team showed an increase in Aβ deposition in diabetic, ZDF rat brains, in response to high glucose. ZDF rats were also shown to have higher levels of BACE1 expressions than those in lean control, ZLC rats. To provide a compelling link between diabetes and AD, the mechanism by which high glucose levels affected APP processing was investigated using mouse hippocampal neuron and SK-N-MC cells.

Using the QIAGEN QuantiNova SYBR Green PCR Kit the group was able to demonstrate via real-time PCR gene expression analysis that high glucose conditions increases expression of BACE1 through upregulation of HIF-1α expression. LXRα/ABCA1 were also upregulated in the presence of high glucose and shown to stimulate BASE1 by recruiting it to lipid rafts, where APP cleavage to Aβ occurs.

  1. Further studies and proof that uncontrolled diabetes can lead to serious neurological impairment could spur early diagnosis programs, and go a long way towards improved compliance with diabetes treatments. This would have a profound effect not only on the diabetes morbidity and mortality rate2, but also on the prevalence of Alzheimer’s disease – having the potential to reduce Alzheimer’s incidence by up to 40%.

You can read more about this study in Nature Scientific Reports here. Explore our Alzheimer’s pathway to build and present your own findings or visit our online research center and advance your understanding in Alzheimer’s disease and neurodegenerative diseases.

References:

  1. 1)   Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med  2006, 3(11):e442.
  2. 2)   Ford ES. Trends in the control of risk factors for cardiovascular disease among adults with diagnosed diabetes: findings from the National Health and Nutrition Examination Survey 1999-2008*. J Diabetes  2011, Dec; 3(4):337-47.
  3. 3)   Ott A. et al.: Diabetes mellitus and the risk of dementia: The Rotterdam study. Neurology 1999, 10: 1937–1942.
  4. 4)   Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297: 353-356.
  5. 5)   T. Ohara, Y. Doi, T. Ninomiya, et al. Glucose tolerance status and risk of dementia in the community. The Hisayama Study. Neurology 2011, 77:1126.
Anissa Heyse

Anissa Heyse is a Scientific Writer for QIAGEN. Formerly a regular columnist at Laboratory Focus Magazine, Anissa has broad experience writing about relevant life science topics. Anissa trained as a molecular biologist at Queen’s University in Canada and continued with her Master’s studies at the University of Toronto, studying transcriptional regulation of prolactin expression. Anissa brings insights from an MBA in International Business and over 10 years in the biotech industry in research, marketing and communications.

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