# Role of Microglia in Adult Onset Luekoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $41,987

## Abstract

Project Summary
Adult Onset Leukoencephalopathy with Axonal Spheroid and Pigmented Glia (ALSP) is a neurodegenerative
disorder leading to presenile dementia. While devastating, our lack of understanding of the disease has hindered
the development of effective treatments. ALSP is characterized by ablation of the white matter, cortical atrophy
in the frontal and parietal lobes, epileptic seizures as well as spastic paraplegia. Importantly, genome wide
linkage analyses have linked mutations in the kinase domain of Colony stimulating factor 1 receptor (CSF1R) as
a causative agent towards development of ALSP. CSF1R is primarily expressed by microglia in the homeostatic
brain highlighting the potential for microglia to be critically involved in ALSP pathogenesis. Interestingly, a CSF1R
haploinsufficient (CSF1R+/-) mouse model of ALSP presents with increased number of microglia similar to a
multitude of neurodegenerative disorders which also present with increases in microglial number. Preliminary
studies comparing Wild-type (WT) and CSF1R+/- mice revealed performance deficits in behavioral tasks of
CSF1R+/- mice. Immunohistochemical analyses found alterations to protein expressions in CSF1R+/- mice –
increased levels of neuronal Lamp1 (one of the top differentially expressed genes in our RNAsequencing data)
and decreased number of synaptic elements Bassoon, Synaptophysin and Sv2A. As it stands, these data, and
more, hint at microglia playing some role in mediating the disease. What that role is, however, remains to be
discovered. In this proposal I seek to 1) create a timecourse of microglial proliferation and apoptosis during early
postnatal development and adulthood to investigate the mechanism for increased microglia densities 2)
characterize microglia transcriptional profiles during these time points and 3) identify whether microglia are
involved in disease pathogenesis by creating mouse lines that have CSF1R heterozygosity specifically in
microglia and neurons as recent evidence has revealed CSF1R expression in neuronal subtypes as well as
neural progenitor cells. Collectively, this proposal will elucidate the role of microglial CSF1R signaling in the
development of ALSP pathology, providing insight into novel mechanisms governing neurodegeneration and
ALSP progression and setting the groundwork for future studies that could lead to the development of disease
modifying therapies.

## Key facts

- **NIH application ID:** 10143061
- **Project number:** 5F31NS111882-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Miguel Angel Arreola
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,987
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143061

## Citation

> US National Institutes of Health, RePORTER application 10143061, Role of Microglia in Adult Onset Luekoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (5F31NS111882-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10143061. Licensed CC0.

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