# Role of mast cell traps in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $390,574

## Abstract

PROJECT SUMMARY/ABSTRACT
In the Parent R01, HL147562 (PI: Gupta), we have identified a “hyperactivated” state involving mast cell,
vascular, inflammatory, and neural systems in sickle cell disease (SCD). Mast cells reside in tissues, cohabiting
with nerves and vasculature, promoting direct neurovascular and neuroinflammatory interactions. Extracellular
release of DNA and citrullinated histones from mast cells in a sickle microenvironment mimics extracellular traps
(ETs) released by granulocytes to ensnare pathogens. In the Parent R01, we are examining how mast cell
activation replete with ETs contributes to vascular dysfunction, axonal injury and increased blood brain barrier
permeability leading to hyperalgesia in SCD. In this Supplement proposal, we will examine if similar mast
cell activation-mediated mechanisms contribute to neuronal damage in Alzheimer's disease (AD). AD
involves degeneration of hippocampal neurons and cerebellar Purkinje cells as well as abnormal neurovascular
function, inflammation, and mast cell activation in the brain strikingly similar to SCD as we have demonstrated
in the Parent R01. Moreover, deficits in somatosensory and sensory motor networks correlate with altered gait
and motor function that precede cognitive deficits in aging and AD. Since gait instability leading to falls is a
leading cause of mortality and morbidity in dementia patients, there is a critical need to understand the
neurodegenerative mechanisms underlying gait changes. In humanized sickle mice we have observed
activated mast cells in the parenchyma of brain and Purkinje cell degeneration in the cerebellum correlative to
pain and gait changes. We hypothesize that mast cell extracellular traps contribute to vascular
dysfunction and Purkinje cell damage in the cerebellum leading to gait alterations preceding cognitive
changes in AD. Using mice with AD we will examine our hypothesis through 2 Specific Aims: (1) Are mast cell
extracellular traps and associated vascular dysfunction elevated in AD mice, relative to WT age-matched
controls? (2) Does inhibition of mast cells/traps prevent gait imbalance and neuronal and vascular alteration and
attenuate the progression of AD? The novel MouseWalker System and artificial intelligence will quantify gait
characteristics during normal walking, as described by PI Gupta. Since SCD and AD share similar mechanisms
of hemodynamic and metabolic injury, we will examine if mast cell activation/ETs cause vascular dysfunction by
monitoring cerebral perfusion and metabolism in vivo in the cerebellum and cortex of mice with AD using optical
imaging technology developed by Co-Is Akbari and Wilson. We anticipate that this proof of principle proposal
will demonstrate that unique traps and activation of mast cells contribute to neuronal damage and vascular
dysfunction in the brain leading to impaired gait. Since gait changes precede cognitive impairment in AD, it can
be used to monitor disease progression using remote sensing ...

## Key facts

- **NIH application ID:** 10499962
- **Project number:** 3R01HL147562-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Kalpna Gupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,574
- **Award type:** 3
- **Project period:** 2019-04-04 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499962

## Citation

> US National Institutes of Health, RePORTER application 10499962, Role of mast cell traps in Alzheimer's disease (3R01HL147562-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10499962. Licensed CC0.

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