Molecular determinants of paired helical filament assembly and its therapeutic implications in Alzheimer's disease

Abstract

SummaryStudies of Alzheimer's disease have pointed to loss of the normal microtubule associated protein tau and accumulation of pathological paired helical filaments as strong discriminators for cognitive impairment. The most likely explanation is that the redistribution of tau protein into PHFs is associated with a failure of axonal transport in cortico-cortical association circuits through failure to maintain axonal tubulin in the polymerized state within pyramidal cells. Current understanding of and attempts to translate the key pathogenetic steps in tau pathology as they occur in the human brain are reviewed Although the phosphorylation hypothesis has dominated the application of molecular and cell biological methods, there are substantial difficulties with this account when it has been tested in clinico-pathological studies. The present review develops a more pragmatic view of PHF assembly, that it is in principle an amyloidosis, since more than 80% of the tau protein found PHFs is in the form of detergent insoluble protease-resistant polymers of molecules which have undergone substantial proteolytic processing in the course of polymerization. These molecules have also undergone a characteristic conformational shift in the course of polymerization, and acquire binding sites for planar dyes. The theoretical stance which best fits this data is that which has been proposed in the Prion diseases. A variety of factors may act to initiate a pathological conformational change which is then propagated because of the capacity of the modified form of the molecule to seed the polymerization of the normal form. Whatever the ultimate causes, the process can be shown to progress exponentially in the human brain. Pharmaceutical blockade of pathological redistribution of tau protein into PHFs would represent a desirable pharmaceutical target, since it is likely to represent a major component of the final common molecular substrate of clinical dementia of the Alzheimer-type.