Biochemistry of altered brain proteins in Alzheimer's disease.

Abstract

In contrast to other unsolved diseases of the human brain, Alzheimer's disease (AD) presents features that make it particularly amenable to studies of pathogenesis at the molecular level. The progressive dysfunction of limbic and association cortices in patients with AD is accompanied by the formation of unusual intraneuronal and extracellular proteinaceous filaments. These striking structural changes of neurons, their processes, and adjacent cerebral microvessels provide a cytopathological signature of the disease, a feature often lacking in other neurodegenerative disorders. The filamentous lesions have served as a starting point for much of the recent progress in deciphering macromolecular alterations in AD. The density and distribution of these lesions correlate to a considerable but not complete degree with several phenotypic features of AD, including degree of intellectual impairment, extent of neuronal loss in hippocampus and certain other brain regions, and decline of neurotransmitter markers, particularly cortical choline acetyltransferase activity. Alzheimer's disease also shares certain phenotypic characteristics with a common chromosomal abnormality, Trisomy 21 (Down's syndrome). The fact that the characteristic cerebral lesions of AD accumulate in highly similar fashion in the brains of virtually all Down's syndrome subjccts at an early age has provided valuable clues to the pathogenesis of AD. Another advantage, not yet fully exploited, that accrues from the study of Alzheimer's disease is the fact that similar structural changes in the cortical neuropil and micro vessels occur spontaneously and progressively during