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 fibril s. Amyloidogenic proteins have been implicated in several types of age -related pathologic changes. For example, transthyretin amyloid accumu lation in the heart can lead to cardiac failure, while beta-amyloid de position within the microvasculature and gray matter of the brain is l inked to cerebral hemorrhage and neuronal death. Over the course of ev olution protein structures have developed that largely resist such agg regation. Spontaneous chemical modifications correlated with the norma l aging process, however, including the deamidation, isomerization, an d racemization of asparaginyl and aspartyl residues, as well as the ox idation and glycation of various amino acid residues, may contribute t o amyloid formation by altering protein structure. In fact, a recent c hemical analysis of neuritic plaque and vascular beta-amyloid deposits from the brains of Alzheimer's disease victims has revealed that the majority of the aspartyl residues in beta-amyloid are in the isomerize d and/or racemized configuration. Although enzymes exist that can reve rse at least part of this damage for intracellular proteins, the accum ulation of extracellular proteins containing altered residues might co ntribute to the deterioration of heart, brain, and other tissues that occurs with aging and disease.