# Regulation of cellular functions by the plasminogen receptor, Plg-RKT: Administrative Supplement

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $130,170

## Abstract

Relevance to Alzheimer’s Disease: Alzheimer’s Disease (AD) is a fatal, progressive neurodegenerative
disease primarily affecting the elderly. Because of the aging population, AD is the sixth leading cause of death
in the United States and is the only disease among the top ten causes of death that has no cure. AD is also the
most common cause of dementia in the United States. AD is characterized by brain atrophy, amyloid plaques
(composed of extracellular deposits of aggregated Aβ peptide), neurofibrillary tangles (composed predominantly
of tau protein), neuron and synapse loss and dystrophic neurites. In addition to neuronal loss, evidence from
both clinical and experimental studies strongly supports a key role for inflammation in the development of AD
and the cognitive dysfunction of AD, and the role of microglial activation and macrophage activation in the
progression of AD is being increasingly appreciated. Conditional depletion of plasminogen in peripheral blood is
highly protective from Aβ deposition and the neuroinflammatory response and is accompanied by decreased
microglial/macrophage activation and decreased numbers of perivascular macrophages present in the CNS in
the 5XFAD Alzheimer’s Disease mouse model. A major gap in knowledge is the identity of the
microglial/macrophage receptor mediating effects of plasminogen deletion on the innate neuroimmune response
in AD. We discovered a novel, transmembrane plasminogen receptor, Plg-RKT. Plasminogen-dependent cell
migration to inflammatory sites is regulated by Plg-RKT. In addition, plasminogen-dependent cytokine release
from macrophages is promoted by Plg-RKT. Microglia express Plg-RKT and perivascular macrophages from wild
type mice show high expression of Plg-RKT. Our long-term goal is to understand mechanisms by which Plg-RKT
regulates physiologic and pathologic processes. Our objectives in this supplementary application are to
determine the effects of Plg-RKT deletion on cognitive function in a murine model of AD and to determine the
effects of Plg-RKT deletion on microglial and macrophage proinflammatory function in a murine model of AD. The
central hypothesis to be addressed is that that Plg-RKT promotes neuroinflammation and neuronal loss in AD
and consequent cognitive dysfunction by promoting microglial/macrophage activation and also by increasing the
presence of perivascular macrophages in the CNS by promoting cell migration. To address our hypothesis, our
specific aims are: 1) To test the hypothesis that Plg-RKT promotes cognitive dysfunction in AD mice and 2) To
test the hypothesis that Plg-RKT promotes microglial and macrophage pro-inflammatory effects in AD mice.
Innovation lies in the investigation of a new paradigm in which Plg-RKT is a crucial focal point for regulation of
neuroinflammation in AD and the recognition of this new paradigm should bring about a major shift in current
thinking regarding mechanisms by which neuroinflammation is regulated. The studies proposed are ...

## Key facts

- **NIH application ID:** 10123802
- **Project number:** 3R01HL081046-14S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Lindsey A Miles
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $130,170
- **Award type:** 3
- **Project period:** 2007-04-06 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123802

## Citation

> US National Institutes of Health, RePORTER application 10123802, Regulation of cellular functions by the plasminogen receptor, Plg-RKT: Administrative Supplement (3R01HL081046-14S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123802. Licensed CC0.

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