Intracranial Adeno-Associated Virus-Mediated Delivery of Anti-Pan Amyloid β, Amyloid β40, and Amyloid β42 Single-Chain Variable Fragments Attenuates Plaque Pathology in Amyloid Precursor Protein Mice

Levites, Yona; Jansen, Karen; Smithson, Lisa; Dakin, Rachel; Holloway, V.; Das, Pritam; Golde, Todd E.

doi:10.1523/jneurosci.2795-06.2006

Cited by 116 publications

(113 citation statements)

References 30 publications

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“…44 The value of scFv antibodies for AD therapeutics, moreover, has precedent in recent findings that an Aβ-directed scFv antibody can attenuate plaque pathology in vivo in Tg AD mice 45,46 and eliminate vascular amyloid in a Tg mouse AD model. 47 In the long run, antibodies that have specificity for the subset of synapse-targeting oligomers described here could provide a powerful resource for disease-modifying therapeutics.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Synapse-Binding Subpopulations of Aβ Oligomers Sensitive to Peptide Assembly Blockers and scFv Antibodies

Velasco¹,

Heffern²,

Sebollela³

et al. 2012

ACS Chem. Neurosci.

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Amyloid β42 self-assembly is complex, with multiple pathways leading to large insoluble fibrils or soluble oligomers. Oligomers are now regarded as most germane to Alzheimer's pathogenesis. We have investigated the hypothesis that oligomer formation itself occurs through alternative pathways, with some leading to synapse-binding toxins. Immediately after adding synthetic peptide to buffer, solutions of Aβ42 were separated by a 50 kDa filter and fractions assessed by SDS-PAGE silver stain, Western blot, immunoprecipitation, and capacity for synaptic binding. Aβ42 rapidly assembled into aqueous-stable oligomers, with similar protein abundance in small (<50 kDa) and large (>50 kDa) oligomer fractions. Initially, both fractions were SDS-labile and resolved into tetramers, trimers, and monomers by SDS-PAGE. Upon continued incubation, the larger oligomers developed a small population of SDS-stable 10−16mers, and the smaller oligomers generated gel-impermeant complexes. The two fractions associated differently with neurons, with prominent synaptic binding limited to larger oligomers. Even within the family of larger oligomers, synaptic binding was associated with only a subset of these species, as a new scFv antibody (NUsc1) immunoprecipitated only a small portion of the oligomers while eliminating synaptic binding. Interestingly, low doses of the peptide KLVFFA blocked assembly of the 10−16mers, and this result was associated with loss of the smaller clusters of oligomers observed at synaptic sites. What distinguishes these smaller clusters from the unaffected larger clusters is not yet known. Results indicate that distinct species of Aβ oligomers are generated by alternative assembly pathways and that synapse-binding subpopulations of Aβ oligomers could be specifically targeted for Alzheimer's therapeutics.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Synapse-Binding Subpopulations of Aβ Oligomers Sensitive to Peptide Assembly Blockers and scFv Antibodies

Velasco¹,

Heffern²,

Sebollela³

et al. 2012

ACS Chem. Neurosci.

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“…Preliminary data from the phase I and II AN-1972 clinical trials suggest that immunotherapy may be effective early in AD, well before amyloid is extensively deposited and an advanced degree of vasculature is compromised (19,51). Recent preclinical studies provide evidence that a reduction of both parenchymal plaques and CAA is achieved upon icv injection of an adeno-associated viral vector that expresses anti-A␤ single-chain variable fragments in neonatal transgenic CRND8 mice (52), or by local application of antibodies onto the cortex of Tg2576 mice at 10 to 13 months of age, when CAA follows a linear mode of progression (53). Our experiments in aged Tg2576 mice, with near-saturating levels of CAA and an abundant plaque pathology (41)(42)(43)(44), augment these findings and demonstrate that icv-targeted delivery of anti-A␤ antibodies not only reduces the behavioral deficit, parenchymal plaques, and associated pathology (eg, astrogliosis, dystrophic neurites), but also provides a previously unexpected opportunity to mitigate CAA and associated micro-hemorrhages despite the advanced disease stage.…”

Section: Discussionmentioning

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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“…Newborn mice (P0) were injected with a thin Hamilton syringe into the lateral ventricle (2 µL of 2 mg ml -1 IgG or POM2 solution into each hemisphere) according to previously reported protocols 36 .…”

Section: Newborn Injectionsmentioning

confidence: 99%

The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein

Sonati

Reimann

Falsig

et al. 2013

Nature

195

289

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Prion infections cause lethal neurodegeneration. This process requires the cellular prion protein (PrP(C); ref. 1), which contains a globular domain hinged to a long amino-proximal flexible tail. Here we describe rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the 1 and 3 helices of the PrP(C) globular domain. Ligands included seven distinct monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of globular domain ligands required neuronal PrP(C), was exacerbated by PrP(C) overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. We also found that neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. We conclude that PrP(C) consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrP(C) mutant, PrP(Δ94-134), indicating that the flexible tail mediates toxicity in two distinct PrP(C)-related conditions. Flexible tail-mediated toxicity may conceivably play a role in further prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides. (Fig. 1b). None of three high-affinity antibodies to the octapeptide repeats (OR, residues 50-90 embedded within the FT) were neurotoxic (Fig. 1b). Antibodies POM3 and D13, which bind the "charged cluster-2" 11 (CC2, residues 95-110), were innocuous at 67 nM but neurotoxic at 200 nM (Fig. 1b). None of the tested antibodies were toxic to Prnp o/o COCS ( Supplementary Fig. 2a). The identity of the targeted epitopes appeared to be a better predictor of PrP C antibody toxicity than their affinity to PrP C , suggesting that neurotoxicity resulted from the interaction of antibodies with specific PrP C domains (Supplementary Table 2).The mechanisms of neurotoxicity were further explored using POM1, a highly toxic antibody targeting the GD. Wild-type (wt) and tga20 COCS lost most granule cells (CGC) within 28 and 14 days post-exposure (dpe) to POM1, respectively (Fig. 2a-c). Controls included POM1-treated Prnp o/o COCS 12 , t...

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Intracranial Adeno-Associated Virus-Mediated Delivery of Anti-Pan Amyloid β, Amyloid β40, and Amyloid β42 Single-Chain Variable Fragments Attenuates Plaque Pathology in Amyloid Precursor Protein Mice

Cited by 116 publications

References 30 publications

Synapse-Binding Subpopulations of Aβ Oligomers Sensitive to Peptide Assembly Blockers and scFv Antibodies

Synapse-Binding Subpopulations of Aβ Oligomers Sensitive to Peptide Assembly Blockers and scFv Antibodies

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

The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein

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