ER stress as the cause for dementia-associated olfactory dysfunction

Columbia University Health Sciences, New York NY

Investigators

Linked publications, trials & patents

Abstract

Summary/Abstract One of the great mysteries in clinical neuroscience is the differential susceptibility to neurodegenerative insults that is exhibited by different neuronal subtypes. Understanding why Alzheimer’s disease (AD) or Amyotrophic Lateral Sclerosis have reproducible patterns of initiation and propagation, and deciphering the exact molecular features that determine a neuron’s tolerance to protein aggregation, will facilitate the development of new therapies and diagnostics. Our discovery that olfactory sensory neurons (OSNs) have high baseline levels of ER stress, determined by the sequence of the chosen olfactory receptor (OR) may provide a surprising answer to these questions. Moreover, our demonstration that levels of ER stress instruct axon guidance specificity via the levels of pro-apoptotic transcription factory Ddit3, may reveal novel mechanisms of AD-related olfactory dysfunction. Thus, in this administrative supplement, we propose to build upon the striking discoveries supported by the parent R01 grant, towards questions related to AD-linked olfactory dysfunction. Since it is well established that anosmia constitutes a prodrome syndrome for AD, emerging as early as 10 years prior to the emergence of cognitive symptoms, we propose that OSNs are exquisitely primed for neurodegeneration due to their high base line of ER stress. Thus, using mouse models for AD, we will explore whether OSNs with highest levels of ER stress and Ddit3, are the most sensitive to human mutations the amyloid precursor protein (hAPP) (Aim1). Further, using a novel translational reporter mouse that measures ER stress levels, we will explore whether hAPP mutants increase the levels of ER stress in mouse OSNs, pushing Ddit3 expression to toxic levels much faster than in CNS neurons that do not have pre-existing ER stress (Aim2). Finally, we will ask whether hAPP- induced changes in ER stress and Ddit3 induce axon guidance mistargeting, through Ddit3-mediated dysregulation of axon guidance gene expression programs, providing molecular understanding to cellular changes that precede amyloid plaque formation and neurodegeneration (Aim3). While the proposed experiments will shed light to the long-standing mystery of AD-related olfactory dysfunction, they will provide novel and general insight to the initial molecular changes that cause circuitry defects and cognitive decline in AD patients. Thus, we propose to use the olfactory system as a model for “accelerated neurodegeneration” which will offer novel insight to the initial, and pharmacologically reversible, cellular defects of dementia and Alzheimer’s disease.