# Structure and function of plexin - co-receptor interactions

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $264,040

## Abstract

Alzheimer's disease (AD) and related dementias, such as Parkinson's, are devastating and ultimately fatal
conditions for which currently there are no cures. Extensive research efforts have been focused on the study of
high risk AD proteins, such as ApoE variants and on the proteins that form amyloid aggregates in the brain,
specifically Aβ. The fundamental molecular mechanisms of AD are still debated. Not only is the
characterization of the disease causing agents important, but also how amyloidogenic proteins such as Aβ
interfere with the normal functions of neuronal cells. Since Plexin and Neuropilins (Nrps) are clearly involved in
the development and maintenance of higher brain functions, a number of recent reports of their involvement in
AD are highly significant. However, early co- immuno-precipitation experiments suggest, rather than prove, a
direct interaction between PlexinA4/Nrp1 and Aβ. Thus, we believe a biophysical approach is needed –using
purified proteins- to directly reveal the interacting protein regions. The proposed side-project is a timely
addition to the parent NEI R01 grant as this grant involves Plexin-Neuropilin complexes and their interactions
with ligands (such as Semaphorin) and other receptors (specifically cMet and VEGFR2). The study of Plexin-
Neuropilin complexes from an AD angle is a new opportunity in our laboratory and it is also the first time we will
work on Aβ a. We posit that the interactions of Aβ with the Neuropilin co-receptor are likely part of the
pathology of AD and the interaction may eventually serve as a biomarker for the early detection of the disease,
thus falling within the scope of the Aging Institute's Alzheimer's initiative.
The working hypothesis of this supplemental project is that the CUB Neuropilin extracellular domain interacts
directly with Aβ and that this interaction inhibits the function of Plexin (and later VEGFR2). The former receptor
is involved in the formation and maintenance of neuronal and vascular cell-cell contacts, while the latter plays a
role in angiogenesis, including in pathogenic blood vessel formation in eye diseases such as age related
macular degeneration (AMD) and retinal degeneration in diabetes. Indeed, the Aβ protein is elevated in the
retina in both AD and AMD and likely contributes to AMD and other retinal pathologies itself.
The synergistic subaims for this supplement request are a) the in vitro validation of Aβξ interactions between
Neuropilin extracellular domains and alongside, b) an in silico discovery/modeling of potential interactions via
molecular dynamics simulations. The modeling will inform on the design of mutations to test the interactions,
also for c) experiments in model cells where we will examine how functions of the Plexin-Neuropilin system are
affected by Aβ binding.
Anticipated outcome and impact: We will understand which protein regions are involved in the interactions,
either from experiments and/or from simulations and this information will...

## Key facts

- **NIH application ID:** 10123831
- **Project number:** 3R01EY029169-03S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** MATTHIAS BUCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $264,040
- **Award type:** 3
- **Project period:** 2018-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123831

## Citation

> US National Institutes of Health, RePORTER application 10123831, Structure and function of plexin - co-receptor interactions (3R01EY029169-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123831. Licensed CC0.

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