# Dissecting the mechanisms of Alzheimer's disease (AD)-related smell loss in a C. elegans AD model

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2023 · $312,625

## Abstract

Project Summary
As a deadly neurodegenerative disorder, Alzheimer's disease (AD) features an age-related progressive brain
atrophy and neuronal loss. Among all pathological markers of AD, intracellular neurofibrillary tangles (NFTs)
composed of hyper-phosphorylated tau proteins and extracellular insoluble amyloid plaques mainly composed
of amyloid (Aβ) peptide are the best characterized. However, numerous late stage clinical trials targeting
amyloid or tau in patients with mild-to-moderate symptomatic AD have failed to modify the disease course. A
potential reason is that even during the intermediate phase of clinical AD, enough pathology already
accumulates and irreversible neuronal loss has occurred. Thus, interventions should be applied as early in the
preclinical phase of AD as possible.
Very recently, rapid smell decline during normal cognition period has been shown to predict subsequent
cognitive impairment, dementia, and smaller gray matter volumes in older adults, indicating that smell loss
might serve as a simple biomarker for early AD detection. However, little is known about the cellular and
molecular mechanisms underlying the AD-related smell loss (knowledge gap). Recently, using a previously
established C. elegans AD model, we found that these AD worms also exhibit significantly accelerated age-
dependent smell loss compared to the age-matched healthy control animals, suggesting that we could use this
C. elegans AD model to study the underlying mechanisms of AD-related smell loss. We will first study the
vulnerability of chemosensory neural circuit during AD pathogenesis (Aim 1). Next, we will investigate the
cellular and molecular mechanisms by which the chemosensory neural circuit rapidly loses its function upon
AD pathogenesis (Aim 2).
More than 80% of C. elegans genes have homologues in humans. Importantly, many AD-related genes have
orthologues in C. elegans such as Amyloid Beta Precursor Protein (apl-1), γ-secretase complex (sel-12, hop-1
and spe-4), and microtubule associated protein MAP2/MAP4/MAPT/Tau (ptl-1). As C. elegans has short
lifespan, fully mapped neural circuits, low maintenance cost, and powerful genetic tools, we expect that our
proposed studies using the C. elegans AD model may provide mechanistic insights into the AD-related smell
loss.

## Key facts

- **NIH application ID:** 10709076
- **Project number:** 3R01AG063766-05S1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Rui Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $312,625
- **Award type:** 3
- **Project period:** 2019-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709076

## Citation

> US National Institutes of Health, RePORTER application 10709076, Dissecting the mechanisms of Alzheimer's disease (AD)-related smell loss in a C. elegans AD model (3R01AG063766-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10709076. Licensed CC0.

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