Alzheimer's disease – synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts

Abstract

Many approaches have been undertaken to understand Alzheimer's disease (AD) but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, there is increasing evidence that the previously so-called "secondary factors" such as a disturbed glucose metabolism, oxidative stress and formation of "advanced glycation endproducts" (AGEs) and their interaction in a vicious cycle are also important for the onset and progression of AD. AGEs are protein modifications that contribute to the formation of the histopathological and biochemical hallmarks of AD: amyloid plaques, neurofibrillary tangles and activated microglia. Oxidative modifications are formed by a complex cascade of dehydration, oxidation and cyclisation reactions, subsequent to a non-enzymatic reaction of sugars with amino groups of proteins. Accumulation of AGE-crosslinked proteins throughout life is a general phenomenon of ageing. However, AGEs are more than just markers of ageing since they can also exert adverse biologic effects on tissues and cells, including the activation of intracellular signal transduction pathways, leading to the upregulation of cytokine and free radical production (oxidative stress). Oxidative stress is involved in various divergent events leading to cell damage, including an increase in membrane rigidity, DNA strand breaks and an impairment in glucose uptake. In addition, other age-related metabolic changes such as depletion of antioxidants or decreased energy production by a disturbed glucose metabolism diminish the ability of the cell to cope with the effects of radical-induced membrane, protein and DNA damage. With our improving understanding of the molecular basis for the clinical symptoms of dementia, it is hoped that the elucidation of the etiologic causes, particularly the positive feedback loops involving radical damage and a reduced glucose metabolism, will help to develop novel "neuroprotective" treatment strategies able to interrupt this vicious cycle of oxidative stress and energy shortage in AD.

Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI

“…A prospective study found that subjects with diabetes mellitus have increased amyloid plaques and neurofibrillary tangles in the hippocampus at autopsy [4], though another post-mortem study did not [40]. In diabetic subjects, accelerated formation of advanced glycation endproducts can cross-link amyloid proteins leading to aggregation into the amyloid plaques Data are given as adjusted differences in hippocampal or amygdalar volume on MRI (ml, 95% CI) per standard deviation (SD) increase in post-load insulin concentration and insulin resistance a Volumes are normalised to average head size [6,41]. In addition, glycation of the microtubule associated protein-tau could lead to formation of neurofibrillary tangles [42].…”

Alpha-lipoic acid as a new treatment option for Azheimer type dementia

“…The positive effects of a-lipoic acid on glucose metabolism and energy balance may also play an important role in the functioning of the neurons. Therefore, the importance of a-lipoic acid in the treatment of dementia was proposed as early as 1998 Mü nch et al, 1998).…”

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

“…In addition, more and more "nonamyloid" and "non-tau" causes have been proposed, including disturbances in the insulin / insulin receptor glycation, inflammation, oxidative stress and dys-regulation of the cell cycle. Detailed descriptions of these "non-amyloid" and "non-tau" causes have been published in extensive reviews by the group of Peter Riederer and his collaborators (Thome et al 1996;Münch et al 1997;Münch et al 1998;Riederer et al 2006;Arendt et al 2010;). …”