# Use of super-resolution microscopy to visualize the interaction between Alzheimer therapeutic antibodies and Aβ aggregates

> **NIH NIH R03** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $165,000

## Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people
worldwide. Current pharmacological treatments for AD are symptomatic and ineffective, and clinical trials of
therapies based on anti-Aβ monoclonal antibodies (mAbs) or secretase inhibitors have been disappointing. One
reason for the recent failures of anti-Aβ therapies, even those begun presymptomatically, is that the Aβ
assemblies that accumulate in AD are conformationally diverse, and currently available mAbs do not target the
primary neurotoxic species. Therefore, it is critical to thoroughly characterize the molecular mechanisms by
which therapeutic mAbs interact with Aβ and influence its assembly, structure, and toxicity.
 It is presumed that AD pathology starts by the binding of neurotoxic Aβ oligomers (Aβo) to receptor
proteins or lipids on the surface of neurons, resulting ultimately in synaptic dysfunction and degeneration. In
previous studies, we have used super-resolution microscopy to directly visualize β-receptor interactions at the
nanometer scale. We find that one documented Aβ receptor, the cellular prion protein, PrPC, specifically inhibits
the polymerization of Aβ fibrils via a unique mechanism in which it binds specifically to the rapidly growing end
of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils
in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these
assemblies. Additional experiments suggest that two other previously described Aβ receptors (FcγRIIb, and
LilrB2) act in a similar fashion. Taken together, our results suggest that neurotoxic signaling by several different
receptors may be activated by common molecular interactions with both fibrillar and oligomeric Aβ ligands.
 The experimental approach used in these studies opens up the possibility of probing the mechanism of
action of other agents that affect Aβ polymerization or toxicity, in particular anti-Aβ mAbs such as those currently
undergoing extensive testing in clinical trials. In this application, we propose to characterize the mechanism of
action of four clinical stage antibodies (aducanumab, gantenerumab, bapineuzumab and solanezumab), as well
as a panel of conformation-dependent antibodies that recognize oligomeric, pre-fibrillar, and fibrillar forms of Aβ.
First, we will measure the effect of these mAbs on Aβ aggregation processes using biochemical assays. Then,
we will take advantage of single molecule, SRM to determine the localization of the mAbs on the individual Aβ
aggregates. In addition, we will directly measure fibril elongation rates, as well as primary and secondary
nucleation processes, in the presence and absence of each mAb. Finally, we will determine how these mAbs
affect the interaction between Aβ and three of its documented receptor proteins; PrPC, FcγRIIb, and LilrB2. This
proposal will lay the groundwork for the design of i...

## Key facts

- **NIH application ID:** 10360508
- **Project number:** 5R03AG070709-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Ladan Amin
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $165,000
- **Award type:** 5
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360508

## Citation

> US National Institutes of Health, RePORTER application 10360508, Use of super-resolution microscopy to visualize the interaction between Alzheimer therapeutic antibodies and Aβ aggregates (5R03AG070709-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10360508. Licensed CC0.

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