# The inflammatory mechanisms underlying olfactory dysfunction in prognosis of TBI progression to dementia

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $644,702

## Abstract

Project Summary
20–68% of traumatic brain injury (TBI) patients exhibit trauma-associated olfactory deficits (OD) which can
compromise not only the quality of life but also cognitive and neuropsychiatric functions. Although post-
traumatic anosmia has been documented in the medical literature for more than a century, neither the
underlying mechanisms nor treatment remain clear. Moreover, the occurrence of TBI significantly increases
risk for the development of Alzheimer’s disease (AD) or non-AD forms of dementia. Recent studies of OD have
focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease
progression. Thus, TBI survivors with OD may be an early sign heralding its progression to dementia. AD
pathogenesis revealed that the peripheral olfactory pathways including the olfactory bulb (OB) are the potential
structural candidates responsible for OD in prodromal AD. Emerging studies have associated OD with the
presence of OB inflammatory response, suggesting that OB pathology may provide a mechanistic link between
TBI and AD or dementia. Recent data indicate that TBI-induced rapid and persistent pro-inflammatory
responses in the OB were accompanied by increased phosphorylated tau and OB atrophy, resulting in early
and persistent olfactory deficits. New data indicate that microglia-mediated inflammation contributed to
neuronal hyperexcitation in the OB which was mitigated in the absence of Hv1, a newly discovered microglial
ion channel required for NADPH oxidase-dependent generation of reactive oxygen species. Based on these
findings and our preliminary data, we hypothesize that early after TBI microglial Hv1-mediated inflammation in
the OB contributes to hyperexcitation of local neurons leading to olfactory dysfunction, thus heralding its
progression to late-onset neurodegeneration.
 With multidisciplinary approaches including the Designer Receptors Exclusively Activated by Designer
Drugs (DREADD)-based chemogenetic inhibition of OB microglia, microglia-specific and inducible Hv1 KO
mice combined with microscopy and biochemical approaches, and comprehensive neurobehavioral testing, we
will examine neuroinflammation and neurodegeneration in the OB in a well-established controlled cortical
impact mouse TBI model and their correlation with OD and late-onset dementia-like behaviors (AIM 1).
Furthermore, powerful in vivo and in vitro electrophysiological approaches will be applied to characterize
detrimental effects of TBI-induced inflammation on network and synaptic functions in the OB (AIM 2). Lastly,
we will determine whether genetic or pharmacological inhibition of inflammatory pathways in the OB through
intranasal delivery mitigates TBI-induced inflammation and neurodegeneration thus improves functional
outcomes (AIM 3).
 Our study will be the first to link olfactory dysfunction to dementia and neurodegeneration following TBI.
Our findings will potentially shed light on developing effective appr...

## Key facts

- **NIH application ID:** 10447477
- **Project number:** 1R01AG077541-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Shaolin Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $644,702
- **Award type:** 1
- **Project period:** 2022-06-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447477

## Citation

> US National Institutes of Health, RePORTER application 10447477, The inflammatory mechanisms underlying olfactory dysfunction in prognosis of TBI progression to dementia (1R01AG077541-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10447477. Licensed CC0.

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