Secretory Form of Alzheimer Amyloid Precursor Protein 695 in Human Brain Lacks β/A4 Amyloid Immunoreactivity

Kametani, Fuyuki; Tanaka, Kunihito; Ishii, Tsuyoshi; Ikeda, Shu‐ichi; Kennedy, Hilary E.

doi:10.1006/bbrc.1993.1230

Cited by 41 publications

(38 citation statements)

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“…In order to shed light on the origin and mechanism of amyloid formation, we are attempting to fully characterize the various derivatives of APP in the brain itself. We have previously reported that the secretory form of APP-695 in human brain and CSF lacks fl/A4 immunoreactivity, suggesting alternative processing of APP to leave the entire Aft sequence behind on the membrane [7,8]. To confirm this result, we have analyzed C-terminal fragments of APP in the membrane fraction of DS brain.…”

Section: Introductionmentioning

confidence: 73%

“…Previously, we reported that some secreted APP-695 in human CSF and brain is produced by an alternative cleavage on the N-terminal side of Aft, and that this alternative cleavage would leave behind a membrane-bound fragment containing the whole of the Aft sequence, which could be further processed to release the amyloid peptide [7,8]. Seubert et al have also reported that a substantial portion of the APP secreted by human mixed brain cell cultures, as well as that present in human CSF is of a novel form cleaved precisely at the amino terminus of Aft [ 17].…”

Section: Resultsmentioning

confidence: 99%

“…The C-terminal one-third of the Aft sequence spans part of the transmembrane domain and N-terminal two-thirds extends into the adjacent extracellular domain of APP [4]. Secretory forms of APP have been detected in brain and cerebrospinal fluid (CSF) [6][7][8]. In previous studies, APP was found to be cleaved in the interior of the Aft sequence, which would preclude amyloid formation [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…One possible source of Aft is cell surface APP that has been reinternalized and metabolized in the lysosome [15,16]. Alternatively, intact Aft is also left behind on the amyloidogenic C-terminal fragment of APP produced by alternative processing at or near the cell surface [7,8,17]. In order to shed light on the origin and mechanism of amyloid formation, we are attempting to fully characterize the various derivatives of APP in the brain itself.…”

Section: Introductionmentioning

confidence: 99%

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Secretory cleavage site of Alzheimer amyloid precursor protein is heterogeneous in Down's syndrome brain

et al. 1994

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A~ ~/A4) is the major constituent of brain amyloid in Alzheimer's disease (AD), Down's syndrome (DS) and normal aged persons. This protein is presumably derived by normal proteolysis from a precursor protein (APP). In this study, C-terminal fragments of APP in a Tris/Triton soluble fraction were partially purified from DS brain by heparin-affinity and reverse phase chromatography, and analyzed by N-terminal amino acid sequencing after SDS polyacrylamide gel electrophoresis and Western blotting. We found at least six different C-terminal fragments including those with the entire ,Aft region. These results suggest that secretory processing of APP is heterogeneous and generates amyloidogenic C-terminal fragments.

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Section: Introductionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Secretory cleavage site of Alzheimer amyloid precursor protein is heterogeneous in Down's syndrome brain

et al. 1994

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“…Three main isoforms of /3-APP (/3-APP695, 751 and 770) produced by alternatively spliced mRNAs from a single gene have been identified, and CNS neurons have particularly high levels of l-APP695 expression, whereas in peripheral tissues, f3-APPs751 and 770 are the predominant forms (Tanaka et al 1989;Golde et al 1990). Moreover, soluble secretory derivatives of these f3-APP molecules have been detected in serum (Bush et al 1992), cerebrospinal fluid (Kennedy et al 1992), brain parenchyma (Kametani et al 1993) and the growth medium of several cell cultures (Andersson et al 1991). The present study has shown that f3-APP and f3-protein amyloid fibrils coexist in both senile plaque and cerebrovascular amyloid deposits.…”

Section: Discussionmentioning

confidence: 99%

Variability of .BETA.-Amyloid Protein Deposited Lesions in Down's Syndrome Brains.

Ikeda

Tokuda

Yanagisawa

et al. 1994

Tohoku J. Exp. Med.

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Neuronal β‐amyloid generation is independent of lipid raft association of β‐secretase BACE1: analysis with a palmitoylation‐deficient mutant

et al. 2012

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β-Secretase, BACE1 is a neuron-specific membrane-associated protease that cleaves amyloid precursor protein (APP) to generate β-amyloid protein (Aβ). BACE1 is partially localized in lipid rafts. We investigated whether lipid raft localization of BACE1 affects Aβ production in neurons using a palmitoylation-deficient mutant and further analyzed the relationship between palmitoylation of BACE1 and its shedding and dimerization. We initially confirmed that BACE1 is mainly palmitoylated at four C-terminal cysteine residues in stably transfected neuroblastoma cells. We found that raft localization of mutant BACE1 lacking the palmitoylation modification was markedly reduced in comparison to wild-type BACE1 in neuroblastoma cells as well as rat primary cortical neurons expressing BACE1 via recombinant adenoviruses. In primary neurons, expression of wild-type and mutant BACE1 enhanced production of Aβ from endogenous or overexpressed APP to similar extents with the β-C-terminal fragment (β-CTF) of APP mainly distributed in nonraft fractions. Similarly, β-CTF was recovered mainly in nonraft fractions of neurons expressing Swedish mutant APP only. These results show that raft association of BACE1 does not influence β-cleavage of APP and Aβ production in neurons, and support the view that BACE1 cleaves APP mainly in nonraft domains. Thus, we propose a model of neuronal Aβ generation involving mobilization of β-CTF from nonraft to raft domains. Additionally, we obtained data indicating that palmitoylation plays a role in BACE1 shedding but not dimerization.

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Secretory Form of Alzheimer Amyloid Precursor Protein 695 in Human Brain Lacks β/A4 Amyloid Immunoreactivity

Cited by 41 publications

References 0 publications

Secretory cleavage site of Alzheimer amyloid precursor protein is heterogeneous in Down's syndrome brain

Secretory cleavage site of Alzheimer amyloid precursor protein is heterogeneous in Down's syndrome brain

Variability of .BETA.-Amyloid Protein Deposited Lesions in Down's Syndrome Brains.

Neuronal β‐amyloid generation is independent of lipid raft association of β‐secretase BACE1: analysis with a palmitoylation‐deficient mutant

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