The mechanism of cerebral accumulation of amyloid protein and aluminum.

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Alzheimer's disease is characterized by extracellular deposition in the brain of amyloid protein. The mechanism of accumulation of amyloid in brain is unknown and no simple model systems that produce extracellular amyloid have been reported. Here we speculate that the amyloid protein is generated from the degradation of amyloid precursor protein in cerebral lysosomes. To study the cellular mechanism of generation of the amyloid protein in the brain, pure and well characterized cerebral lysosomal fraction is needed. Therefore, we attempted to obtain a lysosomal fraction from rat brain which had a higher degree of purity in good yield using Percoll gradients following the swelling of mitochondria in the presence of calcium which would eliminate contamination from small amounts of mitochondria. Cerebral lysosomes were purified 330-fold with a yield of approximately 22%, which the highest reported for any cerebral lysosomal preparation. Burkart et al. (1982) have reported that brain lysosomes may play a major role not only in degrading macromolecules but also in their transport to the deposition site. Therefore, obtaining purified rat cerebral lysosomes should represent an important step in the study of the generation of macromolecules which accumulate in the brain and their secretion and/or transport.