The Deposition of Amyloid Proteins in the Aging Mammalian Brain: Implications for Alzheimer's Disease

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Abstract
Dysfunction and loss of neurons and their processes in Alzheimer's disease is accompanied by the progressive accumulation of intraneuronal and extracellular proteinaceous filaments. Currently available evidence indicates that the principal confirmed constituent of the intraneuronal paired helical filaments (PHF) is the microtubule-associated protein, tau. Whether other neuronal proteins contribute to the PHF remains unresolved. The amyloid filaments found in cerebral and meningeal microvessels and in the centers of senile plaques appear so far to be protein chemically and immunochemically distinct from the intraneuronal PHF. The native precursor of the β-amyloid protein comprising these amyloid filaments has now been identified and characterized in brain, non-neural tissues and cDNA-transfected cells of several species, including humans. It occurs as a heterogeneous group of −105–135 kD membrane-associated proteins. cDNA-trans-fected cells reproduce certain β-amyloid precursor fragment patterns observed in human brain tissue, including a favored and stable 11 kd fragment containing the carboxyl terminus and presumably the β-amyloid region. Circulating forms of the precursor have been specifically detected in human cerebrospinal fluid. Understanding the processing of the β-amyloid precursor protein and the origin of β-amyloid deposits should provide insights into a potentially seminal feature of cortical degeneration in Alzheimer's disease.

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