# A New Model to Dissect the Molecular Mechanisms for ApoE-Associated Lipoprotein Complex Aggregation in the Brain

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

Brain microglia become activated and upregulate pro-(and anti-) inflammatory signaling in response to
neuronal cell damage, injury and invasion of the CNS by microbes. Osteopontin (OPN, secreted
phosphoprotein-1, SPP1), is highly upregulated in Alzheimer’s disease (AD) and several other
neurodegenerative disorders and piqued our interest in pursuing additional mechanistic studies into its function
in the central nervous system. An understanding of the molecular mechanisms that underlie the development of
the neuropathologic changes and inflammatory processes over time in these disorders remains incompletely
understood, and are critical barriers to the development of urgently needed treatments for the growing population
of those affected. Interestingly, a “neurodegenerative” microglia gene signature that includes OPN/SPP1 was
described for AD. We have been using a mouse model of viral infection as the initial disruptor of brain
homeostasis to investigate the role of OPN/SPP1 in neuronal injury and inflammation. We found using
translocator protein (TSPO, [11C-DPA-713]) PET-neuroimaging of buffer controls versus HIV-infected
humanized mice with knockdown of OPN/SPP1 expression or not, that OPN/SPP1 is a master regulator of
microglial inflammatory signaling. A second well characterized marker of activated microglia, Iba-1 was also
found by immunohistochemistry (IHC) to be significantly increased. With the prior link of OPN/SPP1 to the
neurodegenerative microglia phenotype, we tested whether expression of other members of the reported
signature were altered in our mice. To our surprise, we found that antisera against mouse ApoE revealed
abundant staining of neurons and glial cells, as well as plaque-like structures and numerous ApoE-
associated microparticles in the brains of HIV-infected mice expressing OPN/SPP1, but absent or low in
those of HIV-infected OPN-, or OPN+ or OPN- buffer injected mice. We are very excited and believe that our
model system, presents for the first time the opportunity to begin to dissect the molecular mechanisms of
microglial activation and to test novel hypotheses centered on a regulatory role for OPN/SPP1 in ApoE-
associated lipoprotein aggregation and neuropathogenesis. With the central role of microglia in AD, this line
of investigation will fill critical gaps in knowledge needed for the advancement of therapeutic approaches aimed
at microglia dysfunction.

## Key facts

- **NIH application ID:** 10115987
- **Project number:** 3R01NS102006-05S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** AMANDA MARIA BROWN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 3
- **Project period:** 2016-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115987

## Citation

> US National Institutes of Health, RePORTER application 10115987, A New Model to Dissect the Molecular Mechanisms for ApoE-Associated Lipoprotein Complex Aggregation in the Brain (3R01NS102006-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10115987. Licensed CC0.

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