β-Amyloid protein promotes neuritic branching in hippocampal cultures

Whitson, J. S.; Glabe, Charles G.; Shintani, Ellen; Abcar, Antoine; Cotman, Carl W.

doi:10.1016/0304-3940(90)90867-9

Cited by 182 publications

(66 citation statements)

References 16 publications

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“…Furthermore, at nanomolar concentrations, A␤ can serve as a trophic factor (Yankner et al, 1990) and attenuates metal-induced oxidative damage (Zou et al, 2002). These findings are consistent with the trophic and neuroprotective action of A␤ at physiological concentrations (Whitson et al, 1989(Whitson et al, , 1990Yankner et al, 1990;Koo et al, 1993;Singh et al, 1994;Luo et al, 1996). A␤ also protects neurons from death following injection with saline or iron (Bishop and Robinson, 2003) and protects lipoproteins from oxidation in cerebrospinal fluid and plasma (may involve metal ion sequestration) (Atwood et al, 1998;Kontush et al, 2001).…”

Section: Amyloid-␤ and Alzheimer Disease: The Alternate Hypothesissupporting

confidence: 55%

Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses

Lee¹,

Zhu²,

Castellani³

et al. 2007

J Pharmacol Exp Ther

134

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Section: Amyloid-␤ and Alzheimer Disease: The Alternate Hypothesissupporting

confidence: 55%

Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses

Lee¹,

Zhu²,

Castellani³

et al. 2007

J Pharmacol Exp Ther

134

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“…Studies aimed at elucidating the biological effects of A/3 on the nervous system have yielded equivocal results. Addition of synthetic peptides corresponding to the first 28 or 42 amino acids of the Al3 sequence to culture medium resulted in a dose-dependent effect on survival and neurite outgrowth of rat hippocampal neurons (3,4). With a similar paradigm, AP-(1-40) peptide was found to be both trophic and toxic to hippocampal neurons, depending on the peptide dose and maturity ofthe neurons in vitro (5).…”

mentioning

confidence: 79%

Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth.

Koo

Park

Selkoe

1993

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

162

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Progressive deposition of amyloid 3-protein In brain, whether A,B has any physiological role is unknown. Studies aimed at elucidating the biological effects of A/3 on the nervous system have yielded equivocal results. Addition of synthetic peptides corresponding to the first 28 or 42 amino acids of the Al3 sequence to culture medium resulted in a dose-dependent effect on survival and neurite outgrowth of rat hippocampal neurons (3, 4). With a similar paradigm, AP-(1-40) peptide was found to be both trophic and toxic to hippocampal neurons, depending on the peptide dose and maturity ofthe neurons in vitro (5). In such systems, increased evidence favors a role of excitatory amino acids in A,B-induced neurotoxicity (6), possibly because A,B destabilizes calcium homeostasis (7). A recent study further suggested that peptide aggregation may enhance A,B toxicity in cultured hippocampal neurons (8). Finally, two reports suggested that transfection of either full-length APP or its C-terminal 100 residues, both ofwhich contain the AP region, into neural cells may result in cell degeneration upon neuronal differentiation (9, 10).Central to many of these studies is the addition of soluble AP3 in relatively high concentrations to culture medium. In one study, acetonitrile and trifluoroacetic acid were used to solubilize A,B before addition to culture medium (5 show that immobilized A,B has no detrimental effect on neurite outgrowth. On the contrary, in the presence of low amounts of extracellular matrix (ECM) components, A,B promotes neurite outgrowth in a dose-dependent manner. MATERIALS AND METHODSPeptides. Six synthetic peptides were used: AP-(1-40),A,B-(1-28), and A,B-(21-37) (all from the human APP sequence) and, as controls, a 40-residue peptide having all A,B amino acids but randomly scrambled (NH2-VIEVLVGE-LDAFDGHVAGFSHDQKGNHVKGGARYMVSIFE), the 37-residue islet amyloid polypeptide (amylin; Peninsula Laboratories), and a 10-residue substance P peptide (Peninsula Laboratories). All peptides were HPLC purified, and the first four peptides were additionally analyzed by mass spectroscopy. All peptides were dissolved in deionized water at a concentration of 1 mg/ml. A sample of AP3 peptide was aggregated before use by dissolving in phosphate-buffered saline at 10 mg/ml, incubating at 37°C for 48 hr, and storing at 4°C for 1 week. The peptide was resuspended in water at 1 mg/ml just before use. On SDS/PAGE, the sample consisted primarily of mono-and dimeric forms, with smaller amounts of tetrameric aggregates. Substrate Preparation. Tissue culture substrates were prepared under sterile conditions by coating 35-mm Petri dishes with a premixed solution consisting of peptide, ECM, or both. All dishes were coated with peptide concentrations ranging from 0.5 to 5.0 pug/cm2. The ECM component con- §To whom reprint requests should be addressed. 4748The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C...

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“…In vivo, small, stable oligomers of A␤-(1-42) have been isolated from brain, plasma, and cerebrospinal fluid (8 -10) and correlate with the severity of neurodegeneration in AD (11, 12). Thus, although genetic evidence predicts that A␤ is a causative factor in AD, the role of fibrillar and oligomeric A␤ in the pathogenesis of AD remains unclear.Initial in vitro studies suggested that A␤-induced neurotoxicity required the peptide to adopt a fibrillar aggregation state, with unaggregated peptide at low doses actually exhibiting neurotrophic effects (13)(14)(15)(16)(17)(18)). Recent studies demonstrate that non-fibrillar structures, including oligomers and amyloid-derived diffusible ligands (ADDLs) (19 -23), and protofibrils (24 -26) are also neurotoxic.…”

mentioning

confidence: 99%

Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

Dahlgren

Manelli

Stine

et al. 2002

Journal of Biological Chemistry

1,337

1,288

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Genetic evidence predicts a causative role for amyloid-␤ (A␤) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of A␤ are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the consistent production of stable oligomeric or fibrillar preparations of A␤-(1-42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and ϳ40-fold more than unaggregated peptide, with oligomeric A␤-(1-42)-induced inhibition significant at 10 nM. Under A␤-(1-42) oligomer-and fibril-forming conditions, A␤-(1-40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of A␤-(1-42). We applied the aggregation protocols developed for wild type A␤-(1-42) to A␤-(1-42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric preparations of the mutations exhibited extensive protofibril and fibril formation, respectively, but were not consistently different from wild type A␤-(1-42) in terms of inhibition of neuronal viability. However, fibrillar preparations of the mutants appeared larger and induced significantly more inhibition of neuronal viability than wild type A␤-(1-42) fibril preparations. These data demonstrate that protocols developed to produce oligomeric and fibrillar A␤-(1-42) are useful in distinguishing the structural and functional differences between A␤-(1-42) and A␤-(1-40) and genetic mutations of A␤-(1-42). Amyloid-␤ (A␤)1 is derived by the proteolytic processing of amyloid precursor protein (APP), resulting in a peptide predominantly 40 or 42 amino acids in length. Mutations in APP and the presenilins that increase the amount of A␤-(1-42) cause AD (for review, see Ref. 1). Historically, the "amyloid cascade" hypothesis has defined the fibrillization of A␤ into amyloid deposits, a pathologic hallmark of AD, as a toxic gain of function (2). That A␤-(1-42) is more fibrillogenic than A␤-(1-40) fits well with this hypothesis. However, amyloid plaques do not always correlate in number, tempo, or distribution with neurodegeneration or clinical dementia. Thus, recent debate within the AD community has focused on whether fibrillar (amyloid) or soluble oligomers of A␤ are the active species of the peptide that ultimately cause the synaptic loss and dementia associated with AD (3-7). In vivo, small, stable oligomers of A␤-(1-42) have been isolated from brain, plasma, and cerebrospinal fluid (8 -10) and correlate with the severity of neurodegeneration in AD (11, 12). Thus, although genetic evidence predicts that A␤ is a causative factor in AD, the role of fibrillar and oligomeric A␤ in the pathogenesis of AD remains unclear.Initial in vitro studies suggested that A␤-induced neurotoxicity required the peptide to adopt a fibrillar aggregation state, with unaggregated peptide at low doses actually exhibiting neurotrophic effects (13)(14)(15)(16)(17)(18)). Recent studies demonstrate that non-fibrillar structures, including oligomers and ...

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β-Amyloid protein promotes neuritic branching in hippocampal cultures

Cited by 182 publications

References 16 publications

Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses

Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses

Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth.

Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

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