Filamentous proteins in Alzheimer's disease: new insights through molecular biology

Abstract

Recent advances in the study of the neurofibrillary tangles (NFT), neuritic plaques (NP), and cerebrovascular amyloid found in the brain of Alzheimer's disease (AD) victims have greatly expanded our understanding of the molecular biology of this disease. Paired helical filaments (PHF) are the primary intracellular filamentous deposit. They appear to be distinct from normal cytoskeletal proteins, but they do contain a significant component of a microtubule-associated protein called 'tau'. Amyloid fibrils make up the extracellular filamentous deposits in AD. Amyloid fibrils are composed of a small protein of about 43 amino acids which has been sequenced. Some investigators suggest PHF are composed of this same protein, but this remains debatable. Molecular genetic studies have shown that a gene which codes for a larger protein containing the sequence of the 'beta-amyloid protein' exists in many tissues and in many species. Interestingly, this gene is located on chromosome 21 which is also the location of the familial AD gene, but these 2 genes are distinct. Several hypotheses exist on the origin of these abnormal deposits and range from neuronal origin to synthesis outside of the CNS with transportation via the blood. The implications of these recent advances are great and include the possibility of accurate and early antemortem diagnostic tests for AD, as well as therapeutic manipulation of the synthesis, deposition, or removal of these filamentous proteins.