Molecular basis for passive immunotherapy of Alzheimer's disease

Gardberg, A.S.; Dice, Lezlee; Ou, Susan; Rich, Rebecca L.; Helmbrecht, Elizabeth; Ko, Jan; Wetzel, Ronald; Myszka, David G.; Patterson, Paul H.; Dealwis, Chris

doi:10.1073/pnas.0705888104

Cited by 97 publications

(142 citation statements)

References 40 publications

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“…Atomic resolution structures have been reported for microcrystals of short amyloid fragments only (Sawaya et al, 2007). Crystallographic studies of A␤ complexed/fused with other proteins include the following: (1) IDE (insulin-degrading enzyme) in complex with A␤ 40 (Shen et al, 2006), in which only A␤ residues 1-3 and 16 -23 were observed; (2) the immunodominant B-cell epitope of the A␤ 1-8 fragment in complex with murine antibodies, which revealed extended coil-like conformations of the epitope (Gardberg et al, 2007;Miles et al, 2008); and (3) the A␤ 28 -42 fragment fused with the C terminus of ribonuclease Tk-RNase HII, which illustrated a limited ␤-conformation (Takano et al, 2006). Nuclear magnetic resonance (NMR) data interpretations of fibrils formed from different A␤ peptides infer either parallel or antiparallel orientations of the ␤-sheets (Lynn and Meredith, 2000;Egnaczyk et al, 2001;Tycko, 2001).…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease

Streltsov¹,

Varghese²,

Masters³

et al. 2011

J. Neurosci.

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Alzheimer's disease is a progressive neurodegenerative disorder associated with the presence of amyloid-␤ (A␤) peptide fibrillar plaques in the brain. However, current evidence suggests that soluble nonfibrillar A␤ oligomers may be the major drivers of A␤-mediated synaptic dysfunction. Structural information on these A␤ species has been very limited because of their noncrystalline and unstable nature. Here, we describe a crystal structure of amylogenic residues 18 -41 of the A␤ peptide (equivalent to the p3 ␣/␥-secretase fragment of amyloid precursor protein) presented within the CDR3 loop region of a shark Ig new antigen receptor (IgNAR) single variable domain antibody. The predominant oligomeric species is a tightly associated A␤ dimer, with paired dimers forming a tetramer in the crystal caged within four IgNAR domains, preventing uncontrolled amyloid formation. Our structure correlates with independently observed features of small nonfibrillar A␤ oligomers and reveals conserved elements consistent with residues and motifs predicted as critical in A␤ folding and oligomerization, thus potentially providing a model system for nonfibrillar oligomer formation in Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease

Streltsov¹,

Varghese²,

Masters³

et al. 2011

J. Neurosci.

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“…Recognition of the hydrophobic central part is also a strategy pursued in the search for peptide or peptidomimetic inhibitors of A␤ fibrillation (15)(16)(17). Recently, the structures of the antigen binding fragments of two antibodies to the N-terminal A␤ (1)(2)(3)(4)(5)(6)(7)(8) peptide were reported (18). However, the structural basis of interactions with the central and C-terminal parts of A␤ remains elusive.…”

mentioning

confidence: 99%

Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

Hoyer

Grönwall

Jonsson

et al. 2008

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

379

552

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According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-␤ (A␤) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar A␤ assemblies is accompanied by a conformational change toward a high content of ␤-structure. Here, we report the solution structure of A␤(1-40) in complex with the phage-display selected affibody protein ZA␤3, a binding protein of nanomolar affinity. Bound A␤(1-40) features a ␤-hairpin comprising residues 17-36, providing the first highresolution structure of A␤ in ␤ conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar A␤. ZA␤3 stabilizes the ␤-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the A␤ hairpin within a large hydrophobic tunnel-like cavity. Consequently, Z A␤3 acts as a stoichiometric inhibitor of A␤ fibrillation. The selected A␤ conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.A␤-peptide ͉ engineered binding protein ͉ molecular recognition ͉ protein structure ͉ nuclear magnetic resonance

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“…A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16)(17)(18)(19)(20)(21)(22)(23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26).…”

mentioning

confidence: 99%

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Díaz

Šimáková

Jacobson

et al. 2009

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

107

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Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A␤). We have hypothesized that the intrinsic A␤ calcium channel activity of the oligomeric A␤ polymer may be responsible for the neurotoxic properties of A␤, and that A␤ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A␤ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A␤ channel and protect neurons from A␤ toxicity. Both block the A␤ channel with similar potency (Ϸ500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.brain ͉ neurodegeneration ͉ rational drug design ͉ drug ͉ toxicity A lzheimer's disease (AD) is a chronic neurodegenerative disease characterized behaviorally by progressive memory loss, and neuronal degeneration in the cerebral cortex, hippocampus, and elsewhere (1, 2). The neuropathology of AD is characterized by amyloid plaques and neuro-fibrillary tangles. The amyloid plaque material has been found to be composed principally of a 40Ϫ42-residue peptide, called amyloid ␤-peptide, or ''A␤'' (3). Both forms of A␤40/42 have been found to be kill neurons and certain other cells in culture. Altogether, these findings have provided strong support for the hypothesis that AD is due to neurotoxic effects of A␤ on susceptible neurons (4-10).The mechanism of A␤ neurotoxicity has been pursued for decades in hopes of translating such knowledge into a pharmaceutical therapy for AD. Cholinesterase inhibitors were the first generation of such candidate therapeutics (11-15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16-23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26). Yet another alternative has been to reduce the levels of A␤ in the brain by inhibiting the proteolytic enzymes associated with trimming APP into A␤ 40 or 42 (27-31).An entirely different approach to the mechanism of A␤ neurotoxicity has been developed following the observation that oligomers of A␤ peptides themselves formed calcium conducting channels in bilayer membranes in vitro (32)(33)(34)(35), and in intact neurons (36). The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38-42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be respo...

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Molecular basis for passive immunotherapy of Alzheimer's disease

Cited by 97 publications

References 40 publications

Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease

Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease

Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

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