Protein aging Extracellular amyloid formation and intracellular repair

Soluble proteins can undergo spontaneous structural and conformational alterations that lead to their stable aggregation into amyloid fibrils. Amyloidogenic proteins have been implicated in several types of age-related pathologic changes. For example, transthyretin amyloid accumulation in the heart can lead to cardiac failure, while β-amyloid deposition within the microvasculature and gray matter of the brain is linked to cerebral hemorrhage and neuronal death. Over the course of evolution, protein structures have developed that largely resist such aggregation. Spontaneous chemical modifications correlated with the normal aging process, however, including the deamidation, isomerization, and racemization of asparaginyl and aspartyl residues, as well as the oxidation and glycation of various amino acid residues, may contribute to amyloid formation by altering protein structure. In fact, a recent chemical analysis of neuritic plaque and vascular β-amyloid deposits from the brains of Alzheimer's disease victims has revealed that the majority of the aspartyl residues in β-amyloid are in the isomerized and/or racemized configuration. Although enzymes exist that can reverse at least part of this damage for intracellular proteins, the accumulation of extracellular proteins containing altered residues might contribute to the deterioration of heart, brain, and other tissues that occurs with aging and disease.