In vitro aging of ß-amyloid protein causes peptide aggregation and neurotoxicity

Pike, Christian J.; Walencewicz, Andrea J.; Glabe, Charles G.; Cotman, Carl W.

doi:10.1016/0006-8993(91)91553-d

Cited by 828 publications

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“…The biological properties of the two enantiomers were then tested by applying the enantiomers to primary cultures of rat hippocampal and cortical neurons that have previously been used to assay the neurotoxic activity of A␤ (12,18). The all-D-A␤ [25][26][27][28][29][30][31][32][33][34][35] produced visible aggregates in the tissue culture wells and appeared to bind to the surface of neurons equally as well as the all-L-A␤ [25][26][27][28][29][30][31][32][33][34][35] (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Three different lots of the all-L-A␤ [25][26][27][28][29][30][31][32][33][34][35] and two lots of the all-D-A␤ [25][26][27][28][29][30][31][32][33][34][35] were used, and both forms gave similar results (data not shown). The above results show that both peptides have similar physical properties and can only be distinguished by CD analysis where mirror image spectra are generated (data not shown).The biological properties of the two enantiomers were then tested by applying the enantiomers to primary cultures of rat hippocampal and cortical neurons that have previously been used to assay the neurotoxic activity of A␤ (12,18). The all-D-A␤ 25-35 produced visible aggregates in the tissue culture wells and appeared to bind to the surface of neurons equally as well as the all-L-A␤ [25][26][27][28][29][30][31][32][33][34][35] (Fig.…”

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confidence: 99%

“…Cultures were plated at 2.5 ϫ 10 4 cells/cm 2 on poly-L-lysine-treated multiwell plates and maintained in serum-free DMEM supplemented with N-2 components. After two days in vitro, cultures were exposed to the various A␤ peptides for 24 h, after which cell viability was determined on the basis of trypan blue exclusion (12,18). Raw data were statistically compared by analysis of variance followed by Scheffé f-test.…”

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All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

Cribbs

Pike²,

Weinstein³

et al. 1997

Journal of Biological Chemistry

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The amyloidogenic peptide ␤-amyloid has previously been shown to bind to neurons in the form of fibrillar clusters on the cell surface, which induces neurodegeneration and activates a program of cell death characteristic of apoptosis. To further investigate the mechanism of A␤ neurotoxicity, we synthesized the all-D-and all-Lstereoisomers of the neurotoxic truncated form of A␤ (A␤ [25][26][27][28][29][30][31][32][33][34][35] ) and the full-length peptide (A␤ 1-42 ) and compared their physical and biological properties. We report that the purified peptides exhibit nearly identical structural and assembly characteristics as assessed by high performance liquid chromatography, electron microscopy, circular dichroism, and sedimentation analysis. In addition, both enantiomers induce similar levels of toxicity in cultured hippocampal neurons. These data suggest that the neurotoxic actions of A␤ result not from stereoisomer-specific ligand-receptor interactions but rather from A␤ cellular interactions in which fibril features of the amyloidogenic peptide are a critical feature. The promiscuous nature of these ␤-sheet-containing fibrils suggests that the accumulation of amyloidogenic peptides in vivo as extracellular deposits represents a site of bioactive peptides with the ability to provide inappropriate signals to cells leading to cellular degeneration and disease.Alzheimer's disease (AD), 1 vascular dementia, and hereditary cerebral hemorrhage with the Dutch type are diseases that share an invariant pathological feature, the accumulation of an amyloidogenic peptide into insoluble fibrillar extracellular deposits. In all three cases, the major component of the extracellular debris is the ␤-amyloid peptide (A␤) that is derived from the proteolytic processing of the large membraneanchored amyloid precursor protein (APP) encoded by a single gene located on chromosome 21 (1). However, the biological significance of these amyloid deposits has been extensively debated as to whether they are a causative factor of each disease or merely a metabolically inert end product lacking in biological activity. Evidence in support of a causative role for A␤ in neuropathology comes from genetic analysis of the APP gene where several autosomal dominant mutations have been linked with AD and hereditary cerebral hemorrhage with the Dutch type (2, 3). In a recent in vitro study, the ␤-APP 717 mutation consistently caused a significant increase in the percentage of the longer and more amyloidogenic A␤ 1-42 over the shorter A␤ 1-40 (4). Incorporation of this same mutation into a transgenic mouse model yields A␤ deposition and neuropathology that closely parallels that observed in AD (5). Additional in vivo evidence suggesting that the A␤ peptide itself may be biologically active comes from a transgenic model overexpressing A␤ , in which A␤ transgene expression was detected in a variety of peripheral tissues but histopathological changes were restricted to the brain. Moreover, the neurodegeneration was largely limited to the cerebral cortex, ...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

Cribbs

Pike²,

Weinstein³

et al. 1997

Journal of Biological Chemistry

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“…Several studies have implicated free radicals (Behl, 1997) or calcium (Mattson et al, 1992) in the neurotoxic mechanism. A number of studies have shown that A␤ toxicity is dependent on the degree of aggregation of the peptide (Pike et al, 1991;Lorenzo and Yankner, 1994). The process of "aging" A␤ peptides by incubating them for many hours at 37°C has been found to increase amyloid fibril formation and to increase the neurotoxic effects (Pike et al, 1991).…”

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Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

Postuma

Nunan

et al. 2000

Journal of Neurochemistry

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Accumulation of the ␤-amyloid protein (A␤) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism of A␤ toxicity remains unclear. A␤ can bind to the extracellular matrix, a structure that regulates adhesive events such as neurite outgrowth and synaptogenesis. The binding of A␤ to the extracellular matrix suggests that A␤ may disrupt cell-substrate interactions. Therefore, the effect of substrate-bound A␤ on the growth of isolated chick sympathetic and mouse cortical neurons was examined. A␤1-40 and A␤1-42 had dose-dependent effects on cell morphology. When tissue culture plates were coated with 0.1-10 ng/well A␤, neurite outgrowth increased. Higher amounts of A␤ peptides (Ն3 g/well) inhibited outgrowth. The inhibitory effect was related to aggregation of the peptide, as preincubation of A␤1-40 for 24 h at 37°C (a process known to increase amyloid fibril formation) was necessary for inhibition of neurite outgrowth. A␤29 -42, but not A␤1-28, also inhibited neurite outgrowth at high concentrations, demonstrating that the inhibitory domain is located within the hydrophobic C-terminal region. A␤1-40, A␤1-42, and A␤29 -42 also inhibited cell-substrate adhesion, indicating that the effect on neurite outgrowth may have been due to inhibition of cell adhesion. The results suggest that accumulation of A␤ may disrupt celladhesion mechanisms in vivo.

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“…Recent reports showed the activation of muscarinic acetylcholine receptor ml and/or the protein kinase C signal transduction pathway down-regulate /3AP generation and accelerate sAPP formation on non-neuronal cells or cell lines (Buxbaum et al 1990Caporaso et al 1992; Gillespie et al 1992; Nitsch et al 1992; Gabuzda et al 1993). Moreover, several reports suggest flAP and amyloidogenic C-terminal fragments are neurotoxic (Yankner et al 1990; Pike et al 1991; Kowall et al 1992; Mattson et al 1992; Yoshikawa et al 1992). However, it is not still clear (i) why flAP and APP derivatives are toxic specifically to mature or differentiated neurons, (ii) how they act in neurons and (iii) whether overexpressed APP itself disturbs neuronal metabolism in such a case of Down's syndrome.…”

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The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

Kunishita¹,

Ikeda²,

Araki³

et al. 1994

Tohoku J. Exp. Med.

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The effects of f3-amyloid precursor protein (APP) overexpressing on cell metabolisms of cholinergic neuronal hybridoma cell line (SN49) were examined. The cells stably overexpressing APP contained higher amount of GTP binding protein Go and cytosolic inactive protein kinase Ce, and showed less Ca2+ influx through muscarinic acetylcholine receptor ml compared to original and mock cells which had been transfected with a vector alone. The contents of sn-1, 2-diacylglycerol and cycilc AMP were also reduced in the APP transfectants, although the similar changes were observed in the mock cells. These findings strongly suggest that the overexpression of APP affect the transient receptor-mediated ion channel and calcium-related cell metabolisms in neuronal cells.APP overexpression; cholinergic cell line; muscarinic receptor; protein kinase C; GTP binding protein Deposition of f3-amyloid protein (fAP), which is composed of 39-42 of amino acids, in the brain was one of the major pathological hall-marks in Alzheimer's disease and aged Down's syndrome. fAP is generated by the cleavage of its precursor protein (APP 695, 751 and 770), 100-140 KDa integral mambrane proteins produced by three of alternative spliced mRNA from a gene on human chromosome 21. Proteolytic cleavage between residues 595 and 596 of APP695 forms amyloidogenic C-terminal fragments containing /3AP , while it between residue 612 and 163 produces non-amyloidogenic C-terminal fragments containing P3 (Haass et al. 1993). At least three of APP fragments are normally released to extra-cellular space by either so called c -or f3-secretary pathway. That is, secreted APPS (sAPP) and P3 are processed by a-pathway

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In vitro aging of ß-amyloid protein causes peptide aggregation and neurotoxicity

Cited by 828 publications

References 13 publications

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

Substrate‐Bound β‐Amyloid Peptides Inhibit Cell Adhesion and Neurite Outgrowth in Primary Neuronal Cultures

The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

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