Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein

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Abstract

To study the putative precursor proteins (PreA4(695), PreA4(751), and PreA4(770] of Alzheimer's disease A4 amyloid protein, polyclonal and monoclonal antibodies were raised against a recombinant bacterial PreA4(695) fusion protein. These antibodies were used to identify the precursors in different cell lines as well as in human brain homogenates and cerebrospinal fluid (CSF). The precursors are tyrosine-sulfated, O- and N-glycosylated membrane proteins and have half-lives of 20-30 min in cells. Cells express the polypeptides at their surface but also secrete C-terminal truncated proteins into the medium. These proteins are also found in CSF of both Alzheimer's disease patients and normal individuals. The proteins are derived from their cognate membrane-associated forms by proteolysis and have apparently lost the cytoplasmic and the transmembrane domains. Since the latter contributes to the A4 amyloid sequence, it seems possible that this proteolytic cleavage represents the first step in the formation of A4 amyloid deposits.

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Most cited references 27

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Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus

R Tanzi, J Gusella, P. Watkins … (1987)

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The trans Golgi network: sorting at the exit site of the Golgi complex.

Amber G. F. Griffiths, Nadja K. Simons (1986)

The Golgi complex is a series of membrane compartments through which proteins destined for the plasma membrane, secretory vesicles, and lysosomes move sequentially. A model is proposed whereby these three different classes of proteins are sorted into different vesicles in the last Golgi compartment, the trans Golgi network. This compartment corresponds to a tubular reticulum on the trans side of the Golgi stack, previously called Golgi endoplasmic reticulum lysosomes (GERL).

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Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease.

J Gusella, A McClatchey, Anthony L. Komaroff … (1988)

Amyloid B-protein/amyloid A4 is a peptide present in the neuritic plaques, neurofibrillary tangles and cerebrovascular deposits in patients with Alzheimer's disease and Down's syndrome (trisomy 21) and may be involved in the pathogenesis of Alzheimer's disease. Recent molecular genetic studies have indicated that amyloid protein is encoded as part of a larger protein by a gene on human chromosome 21 (refs 6-9). The amyloid protein precursor (APP) gene is expressed in brain and in several peripheral tissues, but the specific biochemical events leading to deposition of amyloid are not known. We have now screened complementary DNA libraries constructed from peripheral tissues to determine whether the messenger RNA encoding APP in these tissues is identical to that expressed in brain, and we identify a second APP mRNA that encodes an additional internal domain with a sequence characteristic of a Kunitz-type serine protease inhibitor. The alternative APP mRNA is present in both brain and peripheral tissues of normal individuals and those with Alzheimer's disease, but its pattern of expression differs from that of the previously reported APP mRNA.