Localization of the putative precursor of Alzheimer's disease-specific amyloid at nuclear envelopes of adult human muscle.

Zimmermann, Katrin; Herget, Thomas; Salbaum, J. Michael; Schubert, Walter; Hilbich, Caroline; Cramer, Matthias; Masters, Colin L.; Multhaup, Gerd; Kang, Jie; Lemaire, H. G.

doi:10.1002/j.1460-2075.1988.tb02822.x

Cited by 70 publications

(18 citation statements)

References 25 publications

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“…Our findings of a perinuclear immunolocalization of APP in fibroblasts and of a patchy distribution at the surface of K562 cells are similar to the localization in the nuclear envelope and plasma membrane reported in human muscle cells and rat neurons [16,22]. However, a definite localization should be provided by immunostaining at the electron microscope.…”

Section: Resultssupporting

confidence: 88%

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The amyloid precursor protein of Alzheimer disease is expressed as a 130 kDa polypeptide in various cultured cell types

et al. 1988

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The vascular and parenchymal amyloid deposits in Alzheimer disease (AD), normal aging and Down syndrome are mainly composed of a 4 kDa polypeptide (A4), which derives from a larger precursor protein (APP). There is evidence that APP is a transmembrane glycoprotein present in most tissues, but the characteristics of APP in intact cells are not yet known. In order to investigate this issue, we examined the immunoreactivity of fibroblasts of human and nonhuman cell lines with antisera raised to synthetic peptides corresponding to A4 and to two other domains of the APP. All three antisera recognized a 130 kDa polypeptide (APP-130) in immunoblots from all cell lines. In fibroblasts, an additional polypeptide of 228 kDa (APP-228) was recognized by the antiserum to A4. In immunoblots of two dimensional gels, APP-130 showed a pl of 6.2, while APP-228 failed to focus in the pH range of 4.7 7.0. Sequential extractions of cells with buffer and with Triton X-100 indicate that APP-130 is extractable with nonionic detergents at high ionic strength, whereas 228 kDa APP is a cystolic component. Immunofluorescence staining is consistent with an intracellular perinuclear and plasma membrane localization. It is concluded that APP-130 and APP-228 are two forms of the APP which result from extensive posttranslational modifications of a smaller original gene product. It is likely that APP undergoes similar posttranslational modifications in different cell types.

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Section: Resultssupporting

confidence: 88%

“…However, scarce and controversial information is available concerning size and subcellular location of APP in intact tissues or cells [16][17][18]. Some of the controversy may be due to attempts to identify APP in postmortem tissue in which proteins may have undergone autolysis.…”

Section: Introductionmentioning

confidence: 99%

The amyloid precursor protein of Alzheimer disease is expressed as a 130 kDa polypeptide in various cultured cell types

et al. 1988

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“…Although the function of the APP is not yet clear, there is evidence that it may be a membrane protein and that it may be important in regulation of cell growth (17,18). These observations are consistent with its demonstrated expression in a wide variety of tissues and animal species (2,3).…”

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confidence: 62%

Mapping of the gene encoding the beta-amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21.

Patterson

Gardiner

Kao

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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authors request that the following correction be noted. Our conclusion that the APP gene maps very near the 21q21/21q22 border is consistent with the mapping by in situ hybridization to the interface of these two chromosomal bands as reported by Blanquet et al. (1,2) and reported in an abstract by Zabel et al. (3). Unfortunately, we were not familiar with this material. Nevertheless, the situation as it stood before our publication involved the mapping ofthe APP gene by in situ hybridization to two different locations on chromosome 21, one of which would have excluded it from the region of the chromosome pathogenic for Down syndrome. In situ hybridization has, in other important cases, led to incorrect mapping of genes. Therefore, other approaches were required. Our paper presents mapping by other, more reliable methods. In addition, our in situ hybridization was confirmed using a completely different and unrelated DNA probe that we had linked physically to the APP locus by using transverse alternating field electrophoresis, so that we have further independent confirmation of our mapping.

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“…APP mRNA is found in nonneural tissues as well as brain (2,17). However, the A4 peptide is most easily demonstrated by immunologic techniques in extracellular amyloid deposits and affected blood vessels of the AD brain (8)(9)(10)(11) (16,19).…”

Section: Discussionmentioning

confidence: 99%

Identification of cellular and extracellular sites of amyloid precursor protein extracytoplasmic domain in normal and Alzheimer disease brains.

Tate-Ostroff

Majocha

Marotta

1989

Proc. Natl. Acad. Sci. U.S.A.

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Information concerning the distribution of various subdomains of the amyloid precursor protein (APP) in brain may illuminate aspects of the normal metabolism of this membrane-associated protein, as well as putative abnormal processing that may occur in Alzheimer disease (AD). We prepared affinity-purified antibody, P2, against an extracytoplasmic APP site and applied it, along with monoclonal antibodies to the j3-peptide, or A4 region, in conjunction with selective cytochemical staining methods, to control and AD tissues. The following was noted: (i) in contrast to A4 epitopes, which are easily demonstrable primarily in extracellular senile plaques of AD patients, the extracytoplasmic P2 antigen was found in association with neurons, glia, and blood vessels in both normal and AD prefrontal cortex; (i) a subset of senile plaques contained both A4 and P2 antigens; (iU) in some instances, P2 antigen occurred as an extracellular deposit in the absence of A4; (iv) the P2 antigen, but not A4, was also associated with corpora amylacea. In addition to identifying the unique cellular distribution of the APP extracytoplasmic antigen, the results support the view that a segment of this domain undergoes processing and deposition at extracellular sites, including a subset of senile plaques.The structure of Alzheimer amyloid precursor protein (APP) cDNA has been determined (1-5) and shown to correspond to a protein of 695 amino acids that has features in common with glycosylated cell-surface receptors (1). Of the APP domains, the A4 (or P-peptide) region consisting of -42 amino acids appears to extend from the extracytoplasmic domain to the transmembrane site (1). Immunologic and biochemical data have firmly established that in the Alzheimer disease (AD) brain the A4 polypeptide is a major component of cerebrovascular and senile plaque amyloid (6)(7)(8)(9)(10)(11). However, no detailed information has been available concerning the cellular or extracellular localization of the extracytoplasmic domain (ECD) of the APP and its distribution with regard to A4 and senile plaques.The present report addresses the issue oflocalization ofthe ECD by means of an affinity-purified antibody, P2, raised to a unique peptide within the extracytoplasmic region of the APP. Both control and AD brains were stained with P2, anti-A4 monoclonal antibodies (mAbs) (10), and anti-glial fibrillary acidic protein, in addition to selective cytochemical counterstains. We report here that an extracytoplasmic APP domain has unique features in both control and AD brains that distinguish it from A4. We report, further, that certain senile plaques of the AD brain contain the extracytoplasmic P2 antigen in addition to the A4 domain and that the P2 antigen alone can accumulate extracellularly.A portion of these data were reported previously in preliminary form (12). (1) was prepared by methods previously described (10). The polypeptide was determined to have a unique sequence as indicated by searches facilitated by BIONET (IntelliGenetics) data bases....

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Localization of the putative precursor of Alzheimer's disease-specific amyloid at nuclear envelopes of adult human muscle.

Cited by 70 publications

References 25 publications

The amyloid precursor protein of Alzheimer disease is expressed as a 130 kDa polypeptide in various cultured cell types

The amyloid precursor protein of Alzheimer disease is expressed as a 130 kDa polypeptide in various cultured cell types

Mapping of the gene encoding the beta-amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21.

Identification of cellular and extracellular sites of amyloid precursor protein extracytoplasmic domain in normal and Alzheimer disease brains.

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