# Immunomodulation targeting abnormal conformation and the influence of apoE

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $463,850

## Abstract

SUMMARY
The neuropathology of AD includes fibrillary amyloid β (Aβ) in plaques, cerebral amyloid angiopathy (CAA),
and hyperphosphorylated tau fibrils in neurofibrillary tangles (NFT). However, the most toxic species are Aβ
and tau oligomers characterized by generic structural β-sheet secondary structure. These misfolded Aβ and
tau conformers are suitable targets for immunological intervention, although numerous clinical trials thus far
have failed due to: 1) autoimmune toxicity; 2) lack of specific concomitant targeting of oligomeric Aβ and tau
species; and 3) Amyloid Related Imaging Abnormalities (ARIA), particularly among apolipoprotein (apo)E4
carriers, thought to be associated with fibrillar vessel amyloid clearance. To overcome these limitations, we
developed innovative antibody combining sites (aβComAb paratopes) that only recognize the dominant β-
sheet secondary structure of misfolded proteins, a generic characteristic of all pathologic oligomers found in
neurodegenerative diseases. Our preliminary results show that some aβComAb combining sites on either IgM
or IgG class can, without side effects, penetrate the BBB of an AD Tg mouse model with pre-existing Aβ and
tau pathology, achieve significant cognitive rescue, reduce levels of Aβ and tau pathological oligomers, and in
a CAA AD Tg mouse model (TgSwDI) act without ARIA-like toxicity (both models on murine apoE
background). In this project, we will test the hypothesis that aβComAbs (IgM or IgG), unlike mAbs directed
against Aβ sequences (6E10), can be infused safely and produce modifying therapeutic effects without
vascular ARIA-like toxicity in 3xTg and the vascular TgSwDI or APP/PS1dE9 mouse models cross-bred
to human apoE2, E3, or E4 backgrounds. Furthermore, we anticipate that the vascular amyloid
proteomes of these mice will resemble those that Projects 1 and 2 associate with different apoE
backgrounds, treatments, and presence or absence of microhemorrhages. This information is critically
needed to elucidate the mechanism associated with ARIA and select aβComAbs paratopes for future clinical
trials. The specific aims are to:
1) Produce and characterize IgM and IgG forms of combining sites (AβComAb paratopes) that specifically
recognize the β-sheet secondary structures of toxic oligomers.
2) Determine the biochemical and histochemical interaction of the four aβComAbs from Aim 1 with the brain
vasculature of peripherally infused TgSwDI mice crossed on KI human ApoE2, E3, and E4 backgrounds.
3) Determine behavioral, histochemical, and biochemical changes after passive immunotherapy with two
AβComAb paratopes on an IgM and an IgG selected from Aim 2, in 3xTg, Tg APP/PS1dE9, and TgSwDI mice
crossed on KI human ApoE2, E3, and E4 backgrounds.

## Key facts

- **NIH application ID:** 10428586
- **Project number:** 5P01AG060882-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Fernando goni
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $463,850
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428586

## Citation

> US National Institutes of Health, RePORTER application 10428586, Immunomodulation targeting abnormal conformation and the influence of apoE (5P01AG060882-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428586. Licensed CC0.

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