Amylosomes and microtubules in the human brain : relationship to aging and the pathogenesis of Alzheimer's disease

There is evidence that amyloid deposition within the brain is of major importance in the pathogenesis of Alzheimer's disease (AD), but the mechanism of this deposition is not known, and several theories are currently under great debate. The present study of intraneuronal changes in the human brain with age and disease suggests a new explanation for amyloid plaque formation in the pathogenesis of AD.This work indicates that intraneuronal inclusions originally observed by Rees (1975), may contain amyloid peptide (Abeta), the beta-pleated form of which is the major component of the amyloid plaques in AD. We have therefore called them amylosomes. Using the techniques of histology, immunohistochemistry, computerized morphology, as well as protein isolation and analysis, we examined the distribution, size, density and chemical composition of amylosomes in the human brain throughout life. Amylosomes appear during early childhood and remain constant in size and number until advanced old age. Their protein content and immunostaining characteristics indicate they contain Abeta, and their dendritic location in regions where AD plaques form suggested a possible role in Abeta transport from the brain to the CSF. We therefore isolated and quantified human brain microtubule proteins (MT) and the dendritic microtubule-associated protein 2 (MAP2), assessed their ability to polymerize in vitro, quantified the MAP2 mRNA with age, and related these results to the apolipoprotein E (APOE) genotype, which is known to modulate the risk of AD. There was an age-related decrease in MT proteins and MAP2 and in their ability to polymerize, that was accelerated in individuals with APOE epsilon4 allele(s), the group at greatest risk of AD. These results are consistent with the proposal that amylosomes play a role in Abeta metabolism, and an age-related decrease in the dendritic MT transport system could lead to retention of amylosomes, within the brain, with deposition of the Abeta and plaque formation as a consequence. This theory can account for most of the important features of AD, and resolves a number of contradictory hypotheses, as well as suggesting relevant area for further investigation. A better understanding of the pathogenesis will hopefully reveal strategies for prevention and treatment of this common and presently incurable disease