ALZHEIMERS-DISEASE - SYNERGISTIC EFFECTS OF GLUCOSE DEFICIT, OXIDATIVE STRESS AND ADVANCED GLYCATION ENDPRODUCTS

Many approaches have been undertaken to understand Alzheimer's disease (AD) but the heterogeneity of the etiologic factors makes it difficul t to define the clincally 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 disturbe d glucose metabolism, oxidative stress and formation of ''advanced gly cation endproducts'' (AGEs) and their interaction in a vicious cycle a re also important for the onset and progression of AD. AGEs are protei n modifications that contribute to the formation of the histopathologi cal 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 o f proteins. Accumulation of AGE-crosslinked proteins throughout life i s a general phenomenon of ageing. However, AGEs are more than just mar kers of ageing since they can also exert adverse biologic effects on t issues and cells, including the activation of intracellular signal tra nsduction pathways, leading to the upregulation of cytokine and free r adical 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 deple tion of antioxidants or decreased energy production by a disturbed glu cose metabolism diminish the ability of the cell to cope with the effe cts of radical-induced membrane, protein and DNA damage. With our impr oving understanding of the molecular basis for the clinical symptoms o f 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 ''neuroprotec tive'' treatment strategies able to interrupt this vicious cycle of ox idative stress and energy shortage in AD.