Immunohistochemical evidence for the derivation of a peptide ligand from the amyloid beta-protein precursor of Alzheimer disease.

Allsop, David; Wong, Caine W.; Ikeda, Shu‐ichi; Landon, Michael; Kidd, M. T.; Glenner, George G.

doi:10.1073/pnas.85.8.2790

Cited by 41 publications

(14 citation statements)

References 23 publications

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“…The NFTs, mainly comprised of the pathologically self-aggregated tau protein, were characterized around the same time [64] or even earlier than the Aβ deposits [65,66]; however, until the presence of NFTs along the hippocampal area was found to be congruous to the cognitive decline seen in AD patients, and even since, tau phosphorylation is generally regarded as a downstream event [67–69]. Several post-translational events of the tau protein, such as phosphorylation [70–72], conformational changes [73,74] and cleavage [18], are specifically noted in AD, possibly resulting from the following pathological behavior of modified tau protein: lack of microtubule associations, migrations to the cell cytoplasm and self-aggregation.…”

Section: Fibrillary Tau Deposition: Cause or Effect?mentioning

confidence: 99%

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Mondragón‐Rodríguez

Basurto-Islas

Lee

et al. 2010

Expert Review of Neurotherapeutics

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Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer's disease and have been the focus of disease etiology and pathogenesis. However, in the larger picture of a complex disease, the precise etiology of the lesions per se, as well as the clinical disease, remain to be defined. In this regard, to date no single process has been identified as a useful target and treatment efforts have shown no meaningful progress. Therefore, alternative ideas that may lead to new and effective treatment options are much needed. KeywordsAlzheimer's disease; amyloid; fibrillary deposits; oxidative stress; tau Amyloid plaques and neurofibrillary tangles (NFTs) are pathological hallmarks of the progression of Alzheimer's disease (AD). The questions of how, why and when they appear are, therefore, pertinent to understanding the disorder and, as a result, research efforts into the relationship between lesion and pathogenesis have been substantial. It is now known that specific molecular events are associated with the development of AD, although their exact relationship to lesion appearance is still controversial. Pathogenic mutations leading, for example, to amyloid-β (Aβ) deposition, are a primary piece of evidence [1][2][3], while a wide range of other metabolic abnormalities have been proposed [4][5][6][7][8]. During early AD stages, cell cycle deregulation has been related to the disease [9,10], which may also contribute to the protein aggregates. Other processes, such as oxidative damage to DNA and RNA, have † Author for correspondence: Tel.: +1 216 368 3670 Fax: +1 216 368 8964 mark.smith@case.edu.For reprint orders, please contact reprints@expert-reviews.com Financial & competing interests disclosureThis work was funded by NIH grant AG026151. Mark A Smith is, or has in the past been, a paid consultant for, owns equity or stock options in and/or receives grant funding from Anavex, Canopus BioPharma, Medivation, Neurotez, Neuropharm, Panacea Pharmaceuticals and Voyager Pharmaceuticals. George Perry is, or has in the past been, a paid consultant for and/or owns equity or stock options in Neurotez Pharmaceuticals, Panacea Pharmaceuticals, Takeda Pharmaceuticals and Voyager Pharmaceuticals. Xiongwei Zhu is a paid Advisory Board member for Medivation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Genetic events: causative, but how? NIH Public AccessPathogenic mutations leading to familial autosomal-dominant AD involve the Aβ precursor protein (APP) gene [22,23], and presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes [24]. Apolipoprotein E (APOE) polymorphisms, sometimes referred to as familial late-onset AD, are not mutations per se, but are a significant predisposing factor [25,26]. In particular, the APOE gene has three isoforms (ε2,...

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Section: Fibrillary Tau Deposition: Cause or Effect?mentioning

confidence: 99%

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Mondragón‐Rodríguez

Basurto-Islas

Lee

et al. 2010

Expert Review of Neurotherapeutics

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“…The ,328-40 antibody (1:125 dilution in lysates and 1:500 dilution in supematants) is a rabbit antiserum raised against X328-40 peptide conjugated to keyhole limpet hemocyanin (15). The (38-17 antibody (1:40 dilution in lysates and 1:160 dilution in supernatants) is a mouse monoclonal antibody (16). The APP676-695 antibody (1:500 dilution in lysates and 1:2000 dilution in supematants) is a rabbit antiserum raised against the synthetic APP676-695 peptide (17) band was identified by autoradiography, excised from the blot, and placed in an Applied Biosystems model 475 gasphase sequencer.…”

Section: Materials and Methods Metabolic Labeling Andmentioning

confidence: 99%

Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.

Busciglio

Gabuzda

Matsudaira

et al. 1993

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

525

334

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The cellular mechanism underlying the generation of -amyloid in Alzheimer disease and its relationship to the normal metabolism of the amyloid precursor protein are unknown. In this report, we show that 3-and 4-kDa peptides derived from amyloid precursor protein are normally secreted. Epitope mapping and radiolabel sequence analysis suggest that the 4-kDa peptide is closely related to full-length P-amyloid and the 3-kDa species is a heterogeneous set of peptides truncated at the ,B-amyloid N terminus. The /3-amyloid peptides are secreted in parallel with amyloid precursor protein. Inhibitors of Golgi processing inhibit secretion of P-amyloid peptides, whereas lysosomal inhibitors have no effect. The secretion of ,B-amyloid-related peptides occurs in a wide variety of cell tpes, but which peptides are produced and their absolute levels are dependent on cell type. Human astrocytes generated higher levels of (3-amyloid than any other cell type examined.These results suggest that ,B-amyloid is generated in the secretory pathway and provide evidence that glial cells are a major source of 3-amyloid production in the brain.The f3-amyloid protein is a cleavage product of the amyloid precursor protein (APP) that accumulates at high levels in the brain in Alzheimer disease, Down syndrome, and some normal elderly persons (1-3). Two major pathways of APP processing have been identified. Normal processing of APP in the secretory pathway occurs by a proteolytic cleavage within the J-amyloid sequence generating a large secreted form of the protein (4) and a smaller membrane-associated C-terminal fragment (5,6). A second pathway of APP metabolism has been identified in the endosomal-lysosomal system resulting in larger potentially amyloidogenic C-terminal fragments of APP (7-9).Recent reports have shown that f-amyloid-related peptides are normally secreted by cultured cells and can be detected in human cerebrospinal fluid (10-12). However, the cellular mechanism of this processing event is unknown.Here we show that soluble f-amyloid peptides are generated in the APP secretory pathway rather than from the degradation of APP in lysosomes. The 2) in the presence of protease inhibitors [leupeptin (5 ,ug/ml)/aprotinin (10 ,g/ml)/antipain (50 ,ug/ml)/pepstatin (5 ,ug/ml)/phenylmethylsulfonyl fluoride (100 ug/ml)] and phosphatase inhibitors (50 mM imidazole/50 mM potassium fluoride/25 mM ,B-glycerophosphate/100 ,uM sodium orthovanadate). Supernatants and lysates of transfected cells were clarified by centrifugation at 3000 x g for 20 min and 100,000 x g for 60 min, respectively, and then incubated with primary antibody for 4 hr at 4°C followed by immunoprecipitation with protein A-Sepharose (Pharmacia) for 12 hr at 4°C. The Sepharose beads were washed six times, resuspended in 2x reducing SDS sample buffer, and boiled for 3 min. The immunoprecipitated proteins were analyzed by SDS/PAGE on a 10% gel or by Tris-Tricine SDS/PAGE on a 10-20% gel (14)

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“…The processing of the parent molecules and/or the extracellular secretion ofthe resulting subunits may vary with species, tissue, age, hormonal status, extent ofphosphorylation (6), etc. Although the APPs may be cell-surface receptors (7,8), some of the peptidic fragments derived from them may be ligands (9) for specific membrane sites.…”

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confidence: 99%

Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer disease.

Flood

Morley

Roberts

1991

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

141

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Immediate post-training intracerebroventricular administration of a synthetic peptide homologous to IB protein of brain amyloid, [Gln"J].B-(1-28), caused amnesia for footshock active avoidance training in mice in a dose-dependent fashion. This effect was specific to memory processing since the peptide did not cause amnesia when injected 24 hr after training nor did it disturb storage or retrieval of older memories. Shorter fragments of the amyloid j3 protein consisting of residues 12-28, 18-28, and 12-20 also were amnestic when given intracerebroventricularly, residues 12-20 being least effective. The hippocampus, a brain structure importantly involved in learning and memory, consistently shows severe pathological changes and deposition ofamyloid in patients with Alzheimer disease. Immediate post-training bilateral intrahippocampal injection of [Gln"]fi-(1-28) produced amnesia at much lower doses than did [Gln"'],3-(1-28) injected intracerebroventricularly. Thus these experimental results suggest a possible direct role of amyloid .3 protein or fragments thereof in an aspect of the spectrum of cognitive deficit in Alzheimer disease.

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Immunohistochemical evidence for the derivation of a peptide ligand from the amyloid beta-protein precursor of Alzheimer disease.

Cited by 41 publications

References 23 publications

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Causes versus effects: the increasing complexities of Alzheimer’s disease pathogenesis

Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.

Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer disease.

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