ABSTRACT
Extensive research to characterize the cytoskeletal protein abnormali ties in a number of age-related neurodegenerative diseases is beginning to elucidate the mode of formation of abnormal inclusions. Understand ing the formation of inclusions may provide important insights into the mechanism(s) of neurodgeneration and death that underlie the functional deficits that clinically define these diseases. Neurofibrillary tangles (NFT) in Alzheimer disease (AD) and progressive supranuclear palsy (PSP), Pick bodies in Pick disease, and Lewy bodies in Parkinson dis ease (PD) are all derived from the neuronal cytoskeleton-i.e., neuro filaments and the microtubule-associated protein τ. Extensive phospho rylation shifts the association of τ from its physiological role, in microtubule stabilization and assembly, to a pathological role of in clusion formation. However, the role of phosphorylation of τ and neurofdaments in defining the properties of the inclusions remains un clear. In particular, the basis for inclusion insolubility, proteolytic re sistance and neurotoxicity has not been defined. By contrast, recent
evidence suggests that adducts of sugar and lipid oxidation products, as well as direct amino acid side-chain oxidations, are involved in crosslinking-a property that underlies insolubility and protease resis tance. In addition to biochemical changes, neurons with inclusions show an antioxidative response indicating that oxidized proteins are neuro toxic. Therefore, regardless of whether oxidative damage is etiological or downstream, agents that reduce oxidative stress may offer one of the first lines of defense to delay or prevent the onset of neurodegenerative diseases.
