The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Aβ peptides

Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Ab) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Ab(1-40), starting from monomeric Ab to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel b-sheet. These structural changes are described in terms of H-bonding rupture/formation, b-strands reorientation and b-sheet elongation. As antiparallel b-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the b-sheet implicating a reorientation of b-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates.

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“…5). This is in agreement with studies reporting that b-hairpin formation is responsible for the aggregation and toxicity [51].…”

Section: Discussionsupporting

confidence: 93%

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh

Cerf

Derclaye

et al. 2010

Cell. Mol. Life Sci.

135

119

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“…Under the conditions tested, Ab altered APP processing in a reversible manner. This response was addressed in different cells types using the biological active domain Ab [25][26][27][28][29][30][31][32][33][34][35] , which shows properties similar to those of naturally occurring Ab 1-40 and Ab 1-42 (the principal component of AD senile plaques; Pike et al, 1995;Xu et al, 2001a,b;Liao et al, 2007). Hence, Ab 25-35 represents a good experimental model with which to study Ab- Fig.…”

Section: Discussionmentioning

confidence: 99%

Intracellular sAPP retention in response to Aβ is mapped to cytoskeleton‐associated structures

Henriques

Vieira

Crespo-López

et al. 2008

J of Neuroscience Research

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Amyloid beta (Abeta) contributes to neurodegeneration in Alzheimer's disease and provides a close association between molecular events and pathology, although the underlying molecular mechanisms are unclear. In the work described here, Abeta did not induce amyloid precursor protein (APP) expression, but APP processing/trafficking was markedly affected. In COS-7 cells, Abeta provokes retention of intracellular sAPPalpha (isAPPalpha). Intracellular holo-APP levels remain unchanged, and extracellular total sAPP increases, although extracellular sAPPalpha alone was not altered significantly. In primary neuronal cultures and PC12 cells, isAPP also increased, but this was mirrored by a decrease in extracellular total sAPP. The isAPP retention was particularly associated with the cytoskeletal fraction. The retention "per se" occurred in vesicular-like densities, negative for a C-terminal antibody and strongly positive for the 6E10 antibody, clearly showing abnormal intracellular accumulation of sAPPalpha in response to Abeta. Our data support a dynamic model for intracellular retention of sAPPalpha as an early response to Abeta exposure. Particularly noteworthy was the observation that removal of Abeta reversed the isAPP accumulation. Mechanistically, these findings disclose an attractive physiological response, revealing the capacity of cells to deal with adverse effects induced by Abeta.

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“…In this biological fluid, A␤-(1-16) appears to constitute a robust biomarker and the most important C-terminally truncated A␤ peptide for discriminating AD from non-demented controls (45). In fact, cerebrospinal fluid A␤-(1-16) likely reflects A␤ brain clearance mechanisms as the peptide exhibits poor aggregation propensity and lacks neurotoxicity (74). Our data demonstrating the additional lack of toxicity of A␤-(1-16) for ECs provides further support for the notion that proteolytic degra-FIGURE 7.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase 2 (MMP-2) Degrades Soluble Vasculotropic Amyloid-β E22Q and L34V Mutants, Delaying Their Toxicity for Human Brain Microvascular Endothelial Cells

Hernández-Guillamón

Mawhirt

Fossati

et al. 2010

Journal of Biological Chemistry

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Patients carrying mutations within the amyloid-␤ (A␤) sequence develop severe early-onset cerebral amyloid angiopathy with some of the related variants manifesting primarily with hemorrhagic phenotypes. Matrix metalloproteases (MMPs) are typically associated with blood brain barrier disruption and hemorrhagic transformations after ischemic stroke. However, their contribution to cerebral amyloid angiopathy-related hemorrhage remains unclear. Human brain endothelial cells challenged with A␤ synthetic homologues containing mutations known to be associated in vivo with hemorrhagic manifestations (A␤E22Q and A␤L34V) showed enhanced production and activation of MMP-2, evaluated via Multiplex MMP antibody arrays, gel zymography, and Western blot, which in turn proteolytically cleaved in situ the A␤ peptides. Immunoprecipitation followed by mass spectrometry analysis highlighted the generation of specific C-terminal proteolytic fragments, in particular the accumulation of A␤-(1-16), a result validated in vitro with recombinant MMP-2 and quantitatively evaluated using deuteriumlabeled internal standards. Silencing MMP-2 gene expression resulted in reduced A␤ degradation and enhanced apoptosis. Secretion and activation of MMP-2 as well as susceptibility of the A␤ peptides to MMP-2 degradation were dependent on the peptide conformation, with fibrillar elements of A␤E22Q exhibiting negligible effects. Our results indicate that MMP-2 release and activation differentially degrades A␤ species, delaying their toxicity for endothelial cells. However, taking into consideration MMP ability to degrade basement membrane components, these protective effects might also undesirably compromise blood brain barrier integrity and precipitate a hemorrhagic phenotype. Cerebral amyloid angiopathy (CAA)3 , the deposition of amyloid in vessel walls of the central nervous system, compromises leptomeningeal and cortical vessels affecting medium and small size arteries and arterioles as well as capillary endothelium. The most common form of CAA is associated with amyloid-␤ (A␤) deposition, particularly in elderly individuals and in patients with Alzheimer disease (AD) (1, 2). In these cases the deposited protein, A␤, is originated by sequential processing of the amyloid precursor protein primarily generating peptides constituted by 40-and 42-amino acid residue-long peptides, A␤40 and A␤42, respectively. For reasons not completely understood, A␤42 is one of the main components of parenchymal amyloid plaques, whereas A␤40 is the predominant species present in vascular deposits (2-4). The fibrillar and compact A␤ deposition in the brain vessel walls has been related to abnormalities in the vasculature including microaneurysms and fibrinoid necrosis (5), which can subsequently compromise the integrity of the blood brain barrier (BBB). Indeed, one of the most relevant pathological consequences of CAA is the development of intracerebral hemorrhages (ICH) usually affecting cortical and subcortical areas. In turn, ICH results in elevated mortality rates a...

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The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Aβ peptides

Cited by 78 publications

References 25 publications

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Intracellular sAPP retention in response to Aβ is mapped to cytoskeleton‐associated structures

Matrix Metalloproteinase 2 (MMP-2) Degrades Soluble Vasculotropic Amyloid-β E22Q and L34V Mutants, Delaying Their Toxicity for Human Brain Microvascular Endothelial Cells

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