# Impact of monocyte origins on amyloid β clearance and inflammatory responses

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $334,000

## Abstract

PROJECT SUMMARY
Peripheral monocytes are of therapeutic interest in Alzheimer’s Disease because they are capable of clearing
fibrillar amyloid β and can be targeted more readily than the brain’s resident microglia, which become defective
in their ability to clear amyloid β plaques and contribute to neuroinflammation in Alzheimer’s patients. Indeed,
peripheral monocytes have been shown to promote amyloid β plaque clearance, reduce neuroinflammation,
preserve synapses and improve cognitive function in Alzheimer’s Disease mouse models. However,
monocytes are heterogeneous, and little is known about the amyloid β responsiveness and neuroprotective
properties of monocyte subsets. We recently demonstrated that functionally distinct classical monocyte
subsets arise independently from granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell
progenitors (MDPs) in mouse bone marrow. Our analysis of GMP- and MDP-derived classical monocyte gene
expression also revealed that MDP-derived monocytes express higher levels of several genes that have been
implicated in amyloid β binding and clearance than their GMP-derived counterparts. In particular, MDP-derived
monocytes express 50-fold more angiotensin converting enzyme (ACE). Our collaborators, Drs. Maya
Koronyo-Hamaoui and Kenneth Bernstein, have previously shown that monocytes overexpressing ACE clear
amyloid β more effectively than wild type monocytes and protect against neurodegeneration following
peripheral administration in Alzheimer’s Disease mice. The central goal of this study is to determine how
monocyte origins impact the ability of peripheral monocytes and macrophages to clear and respond to amyloid
β. We hypothesize that MDP-derived monocytes and macrophages bind and clear amyloid β more effectively
and are less inflammatory than their GMP-derived counterparts. To test this hypothesis, we will derive
monocytes and macrophages from GMPs and MDPs and compare their ability to detect and internalize fibrillar
amyloid β (Aim 1), as well their production of pro- and anti-inflammatory cytokines in response to stimulation
with fibrillar amyloid β (Aim 2). This project will open a new avenue of investigation for the research team,
building on Dr. Goodridge’s research on the origins and functional diversity of monocyte subsets and
expanding the current focus beyond pathogen defense by facilitating a new collaboration to define the
therapeutic implications of monocyte heterogeneity in the context of Alzheimer’s Disease.

## Key facts

- **NIH application ID:** 10499134
- **Project number:** 3R01AI134987-05S1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Helen S Goodridge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $334,000
- **Award type:** 3
- **Project period:** 2022-08-08 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499134

## Citation

> US National Institutes of Health, RePORTER application 10499134, Impact of monocyte origins on amyloid β clearance and inflammatory responses (3R01AI134987-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10499134. Licensed CC0.

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