Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

Shankar, Ganesh M.; Li, Shaomin; Mehta, Tapan; García-Muñoz, Amaya; Shepardson, Nina E.; Smith, Imelda M.; Brett, Francesca; Farrell, Michael; Rowan, Michael J.; Lemere, Cynthia A.; Regan, Ciaran M.; Walsh, Dominic M.; Sabatini, Bernardo L.; Selkoe, Dennis J.

doi:10.1038/nm1782

Cited by 3,224 publications

(3,083 citation statements)

References 31 publications

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“…Addition of four scFv's blocked any Ab42-induced toxicity at the 0 and 21 h time points. These results are consistent with many previous studies that identified the soluble oligomeric Ab42 forms as the toxic species responsible for neuronal cell death and the inhibition of toxicity by antibodies [3][4][5][6]. Although there are no Ab42 oligomers present in the samples of Ab42 alone and Ab42 with scFv's at 0 time point (Fig.…”

Section: Scfv's Block Cytotoxicity Of Ab Oligomerssupporting

confidence: 93%

Conformation‐dependent single‐chain variable fragment antibodies specifically recognize beta‐amyloid oligomers

et al. 2009

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a b s t r a c tIncreasing evidence indicates that beta-amyloid (Ab) oligomers rather than monomers or fibrils are the major toxic agents that specifically inhibit synaptic plasticity and long-term potentiation (LTP) in Alzheimer's disease (AD). Neutralization of Ab oligomeric toxicity was found to reverse memory deficits. Here, we report four single-chain variable fragment (scFv) antibodies isolated from the naive human scFv library by phage display that specifically recognized Ab oligomers but not monomers and fibrils. These conformation-dependent scFv antibodies inhibit both Ab fibrillation and cytotoxicity and bind to the same type of eptitope displayed on the Ab oligomers. Such scFv antibodies specifically targeting toxic Ab oligomers may have potential therapeutic and diagnostic applications for AD.

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Section: Scfv's Block Cytotoxicity Of Ab Oligomerssupporting

confidence: 93%

Conformation‐dependent single‐chain variable fragment antibodies specifically recognize beta‐amyloid oligomers

et al. 2009

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“…1 Unlike Aβ fibrils or plaques, only the presence of Aβ oligomers correlates with the cognitive status of AD. 4,5 Aβ oligomers cause synaptic pathology 1,6 in line with findings that loss of dendritic spines correlates to early morphological changes in AD patients. 7 Many different oligomeric Aβ species have been identified, 8À10 and neurotoxicity has been attributed to Aβ dimers, 6 Aβ dodecamers, 10,11 or others.…”

supporting

confidence: 71%

Molecular Engineering of a Secreted, Highly Homogeneous, and Neurotoxic Aβ Dimer

Müller‐Schiffmann¹,

Andreyeva²,

Horn

et al. 2011

ACS Chem. Neurosci.

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A lzheimer's disease (AD) is the most prevalent neurodegenerative disorder with the amyloid-β-peptide (Aβ) playing a central role in its pathogenesis. 1 Aβ is generated as a 38À43 residue peptide from the amyloid precursor protein (APP) by the proteolytic activity of β-and γ-secretases. 2,3 Aβ assembles into oligomers of various sizes and Aβ plaques, a neuropathological hallmark of AD. 1 Unlike Aβ fibrils or plaques, only the presence of Aβ oligomers correlates with the cognitive status of AD. 4,5 Aβ oligomers cause synaptic pathology 1,6 in line with findings that loss of dendritic spines correlates to early morphological changes in AD patients. 7 Many different oligomeric Aβ species have been identified, 8À10 and neurotoxicity has been attributed to Aβ dimers, 6 Aβ dodecamers, 10,11 or others. A recent study from Shankar et al. 6 has provided solid evidence that natively secreted Aβ dimers purified from post-mortem brains of patients with clinical AD are the predominant species sufficient to cause synaptic pathology. To gain insight into structureÀfunction relationships of Aβ dimers, it is of paramount importance to generate or purify highly homogeneous, distinct species of Aβ oligomers. So far, detailed structural investigations of native Aβ oligomers have been hampered by their low abundance in available transgenic mouse models of AD or AD patient brains, and laborious purification procedures.Synthetic Aβ has been a convenient tool for studying Aβ protein biochemistry, since it can be generated to relatively high purity in large amounts and is therefore readily available for biophysical and structural studies of some aspects of Aβ. However, evidence has accumulated suggesting that synthetic Aβ oligomers are only insufficiently modeling naturally secreted Aβ oligomer functions, even if refolded and purified by laborious procedures. Several studies clearly indicate that the bioactivity of naturally secreted Aβ oligomers from transfected cells is similar to that of AD brain-derived Aβ oligomers, but more than hundred times stronger than that of synthetic Aβ oligomers, when long-term potentiation (LTP) effects are taken as readout. 12 The major difference between natively secreted and synthetic Aβ is that natively secreted Aβ is the result of a highly controlled and quality-checked, cofactor-assisted proteolytic process at low local concentrations, while bulk refolding of synthetic Aβ occurs without regulating cofactors at high local concentrations. Bulk refolding leads to conformational heterogenetiy of refolded Aβ oligomers correlating with different neurotoxicities. 13 Received: February 20, 2011 Accepted: March 11, 2011 ABSTRACT: Aβ oligomers play a key role in the pathophysiology of Alzheimer's disease. Research into structureÀfunction relationships of Aβ oligomers has been hampered by the lack of large amounts of homogeneous and stable material. Using computational chemistry, we designed conservative cysteine substitutions in Aβ aiming at accelerating and stabilizing assembly of Aβ dimers by an intermolecu...

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“…Assembly of Ab monomers leads to soluble aggregates, namely oligomers, presenting b-structure [6]. Many types of Ab oligomers have been described and linked to AD etiology: dimers [7], trimers, tetramers, dodecamers (Ab*56) [8], Ab-derived diffusible ligands (ADDLs), protofibrils and also annular oligomers [9]. Further aggregation gives rise to insoluble fibrils causing extraneuronal deposits in the brain.…”

Section: Introductionmentioning

confidence: 99%

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.

133

119

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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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Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

Cited by 3,224 publications

References 31 publications

Conformation‐dependent single‐chain variable fragment antibodies specifically recognize beta‐amyloid oligomers

Conformation‐dependent single‐chain variable fragment antibodies specifically recognize beta‐amyloid oligomers

Molecular Engineering of a Secreted, Highly Homogeneous, and Neurotoxic Aβ Dimer

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

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