Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease

Höck, Christoph; Konietzko, Uwe; Papassotiropoulos, Andreas; Wollmer, Axel; Streffer, Johannes; Rotz, Ruth C. von; Davey, Gabriela E.; Moritz, Eva; Nitsch, Roger M.

doi:10.1038/nm783

Cited by 274 publications

(184 citation statements)

References 29 publications

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“…2c). Anti-A␤ [1][2][3][4][5][6][7][8][9][10][11] antibody was also bound to denatured APP that did not coincide with some published data where fA␤ 42 was used as an immunogen (60,61). Antigen differences may be responsible for different specificity to the APP molecule.…”

Section: Discussionmentioning

confidence: 99%

Anti-Aβ1–11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers

Mamikonyan

Necula

Mkrtichyan

et al. 2007

Journal of Biological Chemistry

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Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A␤ peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A␤ 1-11 antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A␤ 1-11 antibody prevented aggregation of A␤ 42 and induced disaggregation of preformed A␤ 42 fibrils down to nonfilamentous and nontoxic species. Anti-A␤ 1-11 antibody delayed A␤ 42 oligomer formation but ultimately appeared to stabilize nonfibrillar conformations, including oligomer-like assemblies. The reduced oligomer-mediated cytotoxicity observed upon preincubation of A␤ oligomers with the anti-A␤ 1-11 antibody in the absence of oligomer disaggregation suggests a possible oligomer rearrangement in the presence of the antibody. These in vitro observations suggest that preventive vaccination may protect from AD or may delay the onset of the disease, whereas therapeutic vaccination cannot disrupt the toxic oligomers and may only minimally alleviate preexisting AD pathology. AD4 is characterized by deposition of fibrillar forms of A␤ peptide in senile plaques, appearance of A␤ congophilic deposits and neurofibrillary tangles in the cerebrovasculature, and neuronal loss (1-4). A␤ peptide is cleaved from the amyloid precursor protein (APP) by ␤-and ␥-secretases (5-7) and is thought to play a central role in the onset and progression of AD (8 -10). In AD, the normally soluble A␤ molecule (39 -43 aa) undergoes conformational changes and is deposited as insoluble fibrils, oligomers, and protofibrills. Previously, it was demonstrated that A␤ neurotoxicity requires insoluble fibril formation (11) and that these fibrils serve as inducers of neuronal apoptosis (12). Recently, emphasis has shifted to smaller soluble oligomers of A␤ 42 , such as the 12-mers known as A␤-derived diffusible ligands, increased about 70-fold in AD patients' brains over controls (13). More recently, it was shown that extracellular accumulation of 56-kDa soluble A␤ assembly impairs memory in middle-aged APP/Tg 2576 mice in the absence of neuritic plaques (14). A␤ 42 dimers and trimers naturally secreted from a 7PA2 cell line were also suggested to be responsible for the disruption of cognitive functions (15). Importantly, intraventricular injection of such A␤ 42 small oligomers inhibited long term potentiation in rat hippocampus, and an injection of anti-A␤ monoclonal antibody 6E10 prevented this inhibition (16). It has also been demonstrated that passive immunization with monoclonal antibodies (NAB61) that specifically recognize a pathologic conformation present in A␤ oligomers resulted in a rapid improvement in spatial learning and memory (17).The therapeutic potency of polyclonal and monoclonal anti-A␤ antibodies was documented in different mouse models of AD (18 -25). Collectively, these data suggest that antibodies specific to the N-terminal region of A␤ are capable of reduci...

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Section: Discussionmentioning

confidence: 99%

Anti-Aβ1–11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers

Mamikonyan

Necula

Mkrtichyan

et al. 2007

Journal of Biological Chemistry

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“…Indeed, active or passive vaccination strategies are currently explored for the treatment of amyloid-related diseases (7,8), including AL amyloid (9), Alzheimer's (10), and prion diseases (11,12). Vaccination was found to lead also to conformational antibodies (13)(14)(15). These or other vaccination-derived antibodies have been shown to prevent aggregation (10), clear preexisting tissue deposits (10), repress prion replication (16), or impair aggregate cytotoxicity (13,17,18).…”

mentioning

confidence: 99%

Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils

Habicht

Haupt

Friedrich

et al. 2007

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

205

242

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The formation of amyloid fibrils is a common biochemical characteristic that occurs in Alzheimer's disease and several other amyloidoses. The unifying structural feature of amyloid fibrils is their specific type of ␤-sheet conformation that differentiates these fibrils from the products of normal protein folding reactions. Here we describe the generation of an antibody domain, termed B10, that recognizes an amyloid-specific and conformationally defined epitope. This antibody domain was selected by phage-display from a recombinant library of camelid antibody domains. Surface plasmon resonance, immunoblots, and immunohistochemistry show that this antibody domain distinguishes A␤ amyloid fibrils from disaggregated A␤ peptide as well as from specific A␤ oligomers. The antibody domain possesses functional activity in preventing the formation of mature amyloid fibrils by stabilizing A␤ protofibrils. These data suggest possible applications of B10 in the detection of amyloid fibrils or in the modulation of their formation.neurodegeneration ͉ prion ͉ protein folding

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“…We used a mouse monoclonal IgG 1 , 6E10, that recognizes the N terminus of human A␤ and binds to the monomer, parenchymal plaques, and CAA (19,32,33). In this respect, the A␤-binding properties of 6E10 are similar to the properties of anti-A␤ antibodies generated in subjects immunized with AN1972 in the aforementioned active immunotherapy trial (14,34,35). In addition, 6E10 targets the extra-neuronal soluble oligomer A␤*56 and intraneuronal A␤, both of which are implicated in the decline of cognitive function (31,36,37).…”

mentioning

confidence: 99%

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

Thakker

Weatherspoon

Harrison

et al. 2009

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

121

112

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Although immunization against amyloid-␤ (A␤) holds promise as a disease-modifying therapy for Alzheimer disease (AD), it is associated with an undesirable accumulation of amyloid in the cerebrovasculature [i.e., cerebral amyloid angiopathy (CAA)] and a heightened risk of micro-hemorrhages. The central and peripheral mechanisms postulated to modulate amyloid with anti-A␤ immunotherapy remain largely elusive. Here, we compared the effects of prolonged intracerebroventricular (icv) versus systemic delivery of anti-A␤ antibodies on the behavioral and pathological changes in an aged Tg2576 mouse model of AD. Prolonged icv infusions of anti-A␤ antibodies dose-dependently reduced the parenchymal plaque burden, astrogliosis, and dystrophic neurites at doses 10-to 50-fold lower than used with systemic delivery of the same antibody. Both icv and systemic anti-A␤ antibodies reversed the behavioral impairment in contextual fear conditioning. More importantly, unlike systemically delivered anti-A␤ antibodies that aggravated vascular pathology, icv-infused antibodies globally reduced CAA and associated micro-hemorrhages. We present data suggesting that the divergent effects of icv-delivered anti-A␤ antibodies result from gradually engaging the local (i.e., central) mechanisms for amyloid clearance, distinct from the mechanisms engaged by high doses of anti-A␤ antibodies that circulate in the vasculature following systemic delivery. With robust efficacy in reversing AD-related pathology and an unexpected benefit in reducing CAA and associated micro-hemorrhages, icv-targeted passive immunotherapy offers a promising therapeutic approach for the long-term management of AD.Alzheimer disease ͉ passive immunotherapy ͉ vascular amyloid ͉ microglia ͉ peripheral sink

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Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease

Cited by 274 publications

References 29 publications

Anti-Aβ1–11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers

Anti-Aβ1–11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers

Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils

Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice

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