Alzheimer disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress (e.g., protein oxidation, lipid oxidation, DNA oxidation and glycoxidation) during the course of the disease. Advanced glycation endproducts (AGEs) are present in amyloid plaques in AD, and its extracellular accumulation may be caused by an accelerated oxidation of glycated proteins. AGEs participate in neuronal death causing direct (chemical) and indirect (cellular) free radical production and consequently increase oxidative stress. The development of drugs for the treatment of AD that breaks the vicious cycles of oxidative stress and neurodegeneration offer new opportunities. These approaches include AGE-inhibitors, antioxidants and anti-inflammatory substances, which prevent free radical production.
One of the hallmarks of Alzheimer's disease is the self-aggregation of the amyloid beta peptide (Abeta) in extracellular amyloid fibrils. Among the different forms of Abeta, the 42-residue fragment (Abeta1-42) readily self-associates and forms nucleation centers from where fibrils can quickly grow. The strong tendency of Abeta1-42 to aggregate is one of the reasons for the scarcity of data on its fibril formation process. We have used atomic force microscopy (AFM) to visualize in liquid environment the fibrillogenesis of synthetic Abeta1-42 on hydrophilic and hydrophobic surfaces. The results presented provide nanometric resolution of the main structures characteristic of the several steps from monomeric Abeta1-42 to mature fibrils in vitro. Oligomeric globular aggregates of Abeta1-42 precede the appearance of protofibrils, the first fibrillar species, although we have not obtained direct evidence of oligomer-protofibril interconversion. The protofibril dimensions deduced from our AFM images are consistent with a model that postulates the stacking of the peptide in a hairpin conformation perpendicular to the long axis of the protofibril, forming single beta-sheets ribbon-shaped. The most abundant form of Abeta1-42 fibril exhibits a nodular structure with a ~100-nm periodicity. This length is very similar 1) to the length of protofibril bundles that are the dominant feature at earlier stages in the aggregation process, 2) to the period of helical structures that have been observed in the core of fibrils, and 3) to the distance between regularly spaced, structurally weak fibril points. Taken together, these data are consistent with the existence of a ~100-nm long basic protofibril unit that is a key fibril building block.
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.
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