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

Abstract

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...

Alzheimer's Disease Peptide Epitope Vaccine Reduces Insoluble But Not Soluble/Oligomeric Aβ Species in Amyloid Precursor Protein Transgenic Mice

“…Therefore, the level of oligomeric, toxic forms of A␤ is not reduced in the brain of APP Tg 2576 mice at least when vaccination was initiated in mice with pre-existing AD-like pathology. These differences between reducing insoluble and soluble A␤ 42 in vivo are not connected to the differences in binding affinity of anti-A␤ 1-11 antibodies to these forms of ␤-amyloid as we previously demonstrated (Mamikonyan et al, 2007).…”

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

“…However, given the efficacy of the F(abЈ) 2 fragment alone (55), FcRn may only partially mediate the effects of icv anti-A␤ antibodies. An earlier study precludes another postulated mechanism, namely disaggregation of amyloid, for clearance by 6E10 (61). Rather, it is likely that icv antibodies enter the brain parenchyma and alter a select pool of A␤ species, such as A␤*56 and intraneuronal A␤ (31,36), which in addition to inf luencing cognitive function, may also affect plaque formation.…”

Transthyretin binding to A‐Beta peptide – Impact on A‐Beta fibrillogenesis and toxicity

“…A-Beta peptide (1-42) is toxic to cells and leads to apoptosis and cellular death; previous works performed in vitro and in vivo demonstrated that the oligomeric form of the peptide has the highest toxicity [21]. Here we tested the hypothesis that TTR could protect against this neurotoxicity.…”