p3 peptide, a truncated form of Aβ devoid of synaptotoxic effect, does not assemble into soluble oligomers

Dulin, Fabienne; Léveillé, Frédéric; Ortega, Javier Becerril; Mornon, Jean‐Paul; Buisson, Alain; Callebaut, Isabelle; Colloc’h, N.

doi:10.1016/j.febslet.2008.05.002

Cited by 42 publications

(31 citation statements)

References 40 publications

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“…Our findings of neurotoxicity, channel formation, and increased neuronal calcium uptake by p3 and N9 are consistent with the work of Pike et al (24), who showed that these N-terminally truncated peptides demonstrated enhanced aggregation, neurotoxicity, and fibrilformation. p3 has been reported not to form "soluble oligomers" (36) and our present results support the notion that p3 oligomerizes directly in the membrane to cause toxicity. However, in a double transgenic mouse study with overexpressed ADAM10 and human APP that increased α-secretase activity, AD initiation and progression were limited (37).…”

Section: Discussionsupporting

confidence: 81%

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

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

214

344

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Full-length amyloid beta peptides (Aβ 1-40/42 ) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. However, recent transgenic animal models cast doubt on their direct role in AD pathology. Nonamyloidogenic truncated amyloid-beta fragments and Aβ ) are also found in amyloid plaques of AD and in the preamyloid lesions of Down syndrome, a model system for early-onset AD study. Very little is known about the structure and activity of these smaller peptides, although they could be the primary AD and Down syndrome pathological agents. Using complementary techniques of molecular dynamics simulations, atomic force microscopy, channel conductance measurements, calcium imaging, neuritic degeneration, and cell death assays, we show that nonamyloidogenic Aβ 9-42 and Aβ 17-42 peptides form ion channels with loosely attached subunits and elicit single-channel conductances. The subunits appear mobile, suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in amyloid precursor protein-deficient cells. The channel mediated calcium uptake induces neurite degeneration in human cortical neurons. Channel conductance, calcium uptake, and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus, truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a unique mechanism of AD and Down syndrome pathologies. The toxicity of nonamyloidogenic peptides via an ion channel mechanism necessitates a reevaluation of the current therapeutic approaches targeting the nonamyloidogenic pathway as avenue for AD treatment.atomic force microscopy | molecular dynamics | cell calcium imaging | neurite degeneration and cell death assays | single-channel conductance A myloid-beta peptides (Aβ 1-40/42 ) produced by β-and γ-secretase processing of amyloid precursor protein (APP) in the amyloidogenic pathway are involved in Alzheimer's disease (AD) pathology. Aβ 1-40/42 peptides form β-sheet-rich ordered aggregates and soluble oligomers. Small oligomers are emerging as the predominant toxic species (1-3); the toxicity is believed to be a result of the loss of ionic homeostasis, presumably via ion channels formed in cellular membranes (4, 5). EM images of Aβ oligomers show doughnut-like morphologies (6). Atomic force microscopic (AFM) images of Aβ peptides reconstituted in lipid bilayers show heteromeric (rectangular to hexagonal) ion channel-like structures with a ∼2.0-nm central pore and 8-to 12-nm outer diameters (7,8). Electrophysiological studies show heterodisperse cationselective single-channel conductances (7)(8)(9)(10)(11)(12)(13)(14) that are consistent with features of other amyloid ion channels (6-8).On the other hand, when APP is cleaved by γ-and α-secretases, it forms the nonamyloidogenic pathway generating ∼2.6-kDa fragments (Aβ 17-40/42 ) known as the p3 peptides (15). Cleavage by γ and BACE between Tyr10 and Glu11 generates another...

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Section: Discussionsupporting

confidence: 81%

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Jang

Arce

Ramachandran

et al. 2010

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

214

344

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“…Because it uses an antibody directed to A␤'s N-terminal amino acid residues, it cannot discriminate between A␤1-40, A␤1-42, other A␤ degradation products, and p3 peptide, which is derived from the non-amyloidogenic pathway of APP processing (Dulin et al, 2008). Further, it cannot distinguish large numbers of small oligomers from smaller numbers of large oligomers.…”

Section: Discussionmentioning

confidence: 98%

Specificity and sensitivity of the Abeta oligomer ELISA

Klaver

Patrias

Finke

et al. 2011

Journal of Neuroscience Methods

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“…Some studies indicate that Ab17-42 exhibits enhanced aggregation relative to full-length Ab42 26 and that p3 peptides are prevalent in diffuse deposits and in a subset of dystrophic neurites in AD patients. 27 However, other studies suggest that p3 peptides might be a benign form of amyloid because they lack domains associated with microglial activation, 28 do not form oligomers, the most toxic species of Ab, 18 and do not have negative effects on neuronal synaptic function. 29 Our present study demonstrates that p3 peptides compete with Ab42 for binding to fibrinogen, suggesting that they may attenuate AD pathology.…”

Section: Discussionmentioning

confidence: 99%

“…The inhibitory efficacy of Ab17-42 was confirmed via pulldown assay, where pulldown of fragment D by biotinylated Ab42 was dose-dependently decreased in the presence of nonbiotinylated Ab17-42 ( Figure 2B). Our AlphaLISA and pulldown results indicate that Ab17-40 and Ab17-42, naturally occurring Ab fragments known as p3 peptides, 18 inhibit the Ab42-fibrinongen interaction, suggesting that these peptides may play a physiological role in modulating Ab42-mediated effects on fibrin clots.…”

Section: Identification Of the Fibrinogen-binding Region Within Ab42mentioning

confidence: 99%

Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen

Zamolodchikov¹,

Berk-Rauch²,

Oren

et al. 2016

Blood

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• Binding to fibrinogen is mediated by the central region of Ab42 and is enhanced by its C-terminal residues.• Ab42 binds the aC region of fibrinogen, delaying plasminmediated fibrin cleavage and generating a persistent aC degradation product.The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with b-amyloid (Ab), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models. In this study, we investigated the biochemical and structural details of the Ab-fibrinogen interaction. We identified the central region of Ab42 as the most critical region for the interaction, which can be inhibited by specific antibodies against the central region of Ab and by naturally occurring p3 peptides, Ab17-40 and Ab17-42. X-ray crystallographic analysis revealed that Ab42 binding to fragment D of fibrinogen induced a structural change in the C-terminal region of the fibrinogen b-chain (b384-393). Furthermore, we identified an additional Ab-binding site within the aC region of fibrinogen. Ab binding to this aC region blocked plasmin-mediated fibrin cleavage at this site, resulting in the generation of increased levels of a plasmin-resistant fibrin degradation fragment. Overall, our study elucidates the Ab-fibrinogen interaction and clarifies the mechanism by which Ab-fibrinogen binding delays fibrinolysis by plasmin. These results may facilitate the development of effective therapeutics against the Ab-fibrinogen interaction to treat cerebrovascular abnormalities in

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p3 peptide, a truncated form of Aβ devoid of synaptotoxic effect, does not assemble into soluble oligomers

Cited by 42 publications

References 40 publications

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

Specificity and sensitivity of the Abeta oligomer ELISA

Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen

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