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

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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.