bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.04.20.590412

Relationship between therapeutic activity and preferential targeting of toxic soluble aggregates by amyloid-beta-directed antibodies

Kaplan, J. M.·Gibbs, E.·Coutts, J.·Zhao, B.·Mackenzie, I.·Cashman, N. R.
View original source ↗Export metadata ↓

Abstract

BackgroundAmyloid-beta (A{beta})-directed antibodies tested clinically for therapeutic activity against Alzheimers disease (AD) have shown varying degrees of efficacy. Although all of these antibodies target the A{beta} peptide, their binding profile to different molecular species of A{beta} differs and may underlie the observed variability in clinical outcomes. ObjectiveExplore the relationship between targeting of soluble toxic A{beta} species and therapeutic efficacy. MethodsSurface plasmon resonance (SPR) was used to conduct a side-by-side comparison of the binding of various A{beta}-directed antibodies to monomers and soluble A{beta} oligomers from AD brains. Immunohistochemistry was performed to assess reactivity with plaque. Preclinical activity was assessed in human amyloid precursor protein (APP) transgenic mouse models of AD. ResultsNon-selective, pan-A{beta} reactive antibodies such as crenezumab and gantenerumab, which have failed to produce a clinical benefit, bound all forms of A{beta} tested. In a competition assay, these antibodies lost the ability to bind toxic AD brain oligomers when exposed to monomers. Aggregate-selective antibodies such as aducanumab, lecanemab and donanemab, showed reduced monomer binding and a greater ability to withstand monomer competition which correlated with their reported inhibition of cognitive decline. Of the antibodies in earlier stages of clinical testing, ACU193 and PMN310 displayed the greatest ability to retain binding to toxic AD brain oligomers while PRX h2731 was highly susceptible to monomer competition. Plaque binding was observed with all aggregate-reactive antibodies with the exception of PMN310, which was strictly selective for soluble oligomers. Targeting of oligomers by PMN310 protected cognition and was not associated with microhemorrhages in mouse models of AD. ConclusionsOverall, these results suggest that selectivity for soluble toxic A{beta} oligomers may be a driver of clinical efficacy, with a potentially reduced risk of ARIA if engagement with plaque is minimized.

Source connections

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Kaplan, J. M., Gibbs, E., Coutts, J., Zhao, B., Mackenzie, I., Cashman, N. R.. 2024-04-25. Relationship between therapeutic activity and preferential targeting of toxic soluble aggregates by amyloid-beta-directed antibodies. https://doi.org/10.1101/2024.04.20.590412

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗
bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗
bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗