# Macrophage-lipoprotein Interactions

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $364,153

## Abstract

Abstract
We have characterized a novel process carried out by phagocytes that we have called "digestive
exophagy". We have shown that macrophages and dendritic cells create extracellular, acidified lysosomal
compartments to digest large objects such as aggregates of LDL or dead adipocytes that are too large to be
phagocytosed. We have found that genetic mutations associated with neurodegenerative disorders (e.g.,
frontotemporal dementia and Alzheimer's disease) also affect the digestive exophagy of aggregated LDL
(agLDL), such as that found in atherosclerotic plaques. This is consistent with similar cellular mechanisms
being involved in both cases. In this supplement, we propose to apply the methods we have developed to
study digestive exophagy of amyloid Aβ by microglia. We will also continue to examine mutants identified in
neurodegeneration studies for their effect on digestion of agLDL by macrophages. We have reported that
macrophages lacking progranulin (GRN) have greatly increased exophagy of aggregated LDL. Mutations or
reduced expression of GRN are linked to AD as well as frontotemporal dementia. TLR4 and other signaling
molecules are required for digestive exophagy, and these same signaling pathways are modulated by
TREM2, a protein that is highly expressed in microglia. Mutations in TREM2 are strongly linked to increased
susceptibility for AD.
 Preliminary studies have shown that microglia create similar acidic compartments upon contact with
large aggregates of fAβ, and they secrete lysosomal contents into them. In Aim 1 we will characterize the
mechanism by which microglia degrade large aggregates of fAβ. We expect to confirm preliminary
observations of lysosome secretion and compartment acidification. We will use fluorescently labeled fAβ to
observe and quantify the degradation of fAβ deposits. These studies will be carried out using primary
mouse microglia. In Aim 2 we will analyze signaling mechanisms that regulate lysosome secretion
and degradation of amyloid Aβ by microglia. Interestingly, preliminary data have shown that lack of
Dap12, an effector of TREM2 signaling, in bone marrow macrophages leads to a large increase in lysosome
secretion upon contact with LDL aggregates or Aβ deposits. Similar studies will be carried out in microglia
from wild type and knockout mice contacting Aβ deposits to determine if there is a role for GRN, Trem2,
Dap12, Tlr4 and other proteins. As illustrated by the Dap12 results, proteins identified in the Alzheimer's
studies may reveal new signaling in macrophages to be studied in the parent grant.

## Key facts

- **NIH application ID:** 10117551
- **Project number:** 3R01HL093324-11S1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Frederick R. Maxfield
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,153
- **Award type:** 3
- **Project period:** 2009-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117551

## Citation

> US National Institutes of Health, RePORTER application 10117551, Macrophage-lipoprotein Interactions (3R01HL093324-11S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10117551. Licensed CC0.

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