Production of the Alzheimer Amyloid β Protein by Normal Proteolytic Processing

Shoji, Mikio; Golde, Todd E.; Ghiso, Jorge; Cheung, Tobun T.; Estus, Steven; Shaffer, Lillian M.; Cai, Xiao Dan; McKay, Deborah M.; Tintner, Ron; Frangione, B; Younkin, Steven G.

doi:10.1126/science.1439760

Cited by 1,414 publications

(843 citation statements)

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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

469

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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 principal components of amyloid plaques are the fibrillar aggregates of amyloid-β (Aβ) peptides 3 (39-43 amino acids), which are produced as a result of enzymatic proteolysis of amyloid precursor protein (APP) in neurons and other cells throughout life [4][5][6] . Strong circumstantial evidence from genetics, pathology, biochemical studies and animal models led to the emergence of the Aβ amyloid cascade hypothesis of AD 7,8 .…”

Section: Introductionmentioning

confidence: 99%