Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids

Seubert, Peter; Vigo‐Pelfrey, Carmen; Esch, Frederick; Lee, Michael; Dovey, Harry F.; Davis, D. H. S.; Sinha, Sukanto; Schiossmacher, Michael; Whaley, Justine; Swindlehurst, Cathy; McCormack, Robert; Wolfert, Robert L.; Selkoe, Dennis J.; Lieberburg, Ivan; Schenk, Dale

doi:10.1038/359325a0

Cited by 1,678 publications

(1,024 citation statements)

References 27 publications

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“…On the basis of results from CD and NMR, we first proposed (Barrow & Zagorski, 1991) that the -peptide may normally exist in human biological fluids in a soluble form and that the longer 42-residue peptide results from an abnormal proteolysis. Subsequently, both of our propositions were shown to be correct using both in vivo and in vitro studies (Seubert et al, 1992;Shoji et al, 1992;Busciglio et al, 1993;Suzuki et al, 1994). There are currently no effective treatments for AD, and the current drug development process is often cumbersome, taking an average 8.8 years for approval (Cutler & Sramek, 1995).…”

Section: Discussionmentioning

confidence: 99%

Nicotine Inhibits Amyloid Formation by the β-Peptide

et al. 1996

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The 42-residue -(1-42) peptide is the major protein component of amyloid plaque cores in Alzheimer's disease. In aqueous solution at physiological pH, the synthetic -(1-42) peptide readily aggregates and precipitates as oligomeric -sheet structures, a process that occurs during amyloid formation in Alzheimer's disease. Using circular dichroism (CD) and ultraviolet spectroscopic techniques, we show that nicotine, a major component in cigarette smoke, inhibits amyloid formation by the -(1-42) peptide. The related compound cotinine, the major metabolite of nicotine in humans, also slows down amyloid formation, but to a lesser extent than nicotine. In contrast, control substances pyridine and Nmethylpyrrolidine accelerate the aggregation process. Nuclear magnetic resonance (NMR) studies demonstrate that nicotine binds to the 1-28 peptide region when folded in an R-helical conformation. On the basis of chemical shift data, the binding primarily involves the N-CH 3 and 5′CH 2 pyrrolidine moieties of nicotine and the histidine residues of the peptide. The binding is in fast exchange, as shown by single averaged NMR peaks and the lack of nuclear Overhauser enhancement data between nicotine and the peptide in two-dimensional NOESY spectra. A mechanism is proposed, whereby nicotine retards amyloidosis by preventing an R-helix f -sheet conformational transformation that is important in the pathogenesis of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Nicotine Inhibits Amyloid Formation by the β-Peptide

et al. 1996

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“…But naturally generated Aβ peptides in brain, cerebrospinal fluid (CSF) or the media of cultured cells are considerably more heterogeneous in length (see, e.g [5,19,25,47,50,54,56,64,70]. More importantly, almost all studies of synthetic Aβ peptides have employed concentrations upwards of 1 uM, often 10-40 uM, because the critical concentration allowing relatively rapid assembly of synthetic Aβ40 (the most commonly used peptide) into amyloid fibrils is in the high nanomolar range or greater.…”

Section: Moving From Synthetic Aβ Peptides To Naturally Secreted Aβ Amentioning

confidence: 99%

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

Selkoe

2008

Behavioural Brain Research

912

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SummaryDuring the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid β-protein (Aβ) in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease (AD). The reasons for elevated cortical Aβ42 levels in most patients with typical, late-onset AD are unknown, but based on recent work, these could turn out to include augmented neuronal release of Aβ during some kinds of synaptic activity. Elevated levels of soluble Aβ42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts. We have identified certain APP-expressing cultured cell lines that form low-n oligomers intracellularly and release a portion of them into the medium. We find that these naturally secreted soluble oligomers --at picomolar concentrations --can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats. Aβ trimers appear to be more potent in disrupting LTP than are dimers. The cell-derived oligomers also decrease dendritic spine density in organotypic hippocampal slice cultures, and this decrease can be prevented by administration of Aβ antibodies or small-molecule modulators of Aβ aggregation. This therapeutic progress has been accompanied by advances in imaging the Aβ deposits non-invasively in humans. A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging.

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“…The major C-terminal variants include A␤C40 and A␤C42, which retain C-terminal amino acids identical to those of the secreted A␤1-40 and A␤1-42, respectively (Mori et al, 1992;Miller et al, 1993;Roher et al, 1993a,b). In the parenchymal amyloid deposits, A␤C42 is deposited in greater density than A␤C40 (Iwatsubo et al, 1994, although soluble A␤1-40 is more abundantly secreted than soluble A␤1-42 (Seubert et al, 1992;Dovey et al, 1993;Vigo-Pelfrey et al, 1993;Suzuki et al, 1994). Thus, these distinct A␤ species seem to be metabolized differently and may play different roles in the deposition of A␤.…”

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confidence: 94%

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

et al. 1997

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Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid ␤-protein (A␤), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two A␤ variants, we used an in vivo paradigm in which freshly solubilized A␤1-40 or A␤1-42 was injected into rat brains, followed by examination using Congo red birefringence, A␤ immunohistochemistry, and electron microscopy. In the rat brain, soluble A␤ 1-40 and A␤1-42 formed aggregates, and the A␤1-40 but not the A␤1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the A␤1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the A␤1-42 aggregates contained nonfibrillar amorphous material. Preincubation of A␤1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated A␤1-42, the aggregates remained birefringent in the rat brain. Thus, a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble A␤1-42. To analyze the postsecretory processing of A␤, we used the same in vivo paradigm and showed that A␤1-40 and A␤1-42 were processed at their N termini to yield variants starting at pyroglutamate, and at their C termini to yield variants ending at Val40 and at Val39. Thus the normal rat brain could produce enzymes that mediate the conversion of A␤ 1-40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of A␤ deposition evolving into amyloid plaques in AD.

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Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids

Cited by 1,678 publications

References 27 publications

Nicotine Inhibits Amyloid Formation by the β-Peptide

Nicotine Inhibits Amyloid Formation by the β-Peptide

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

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