Abstract:

Although phylogenetically ancient, the olfactory system has received less attention than other sensorial systems. However, olfactory dysfunction is considered an early prodromal event in neurodegenerative diseases (NDs), which may vary from severe smell loss (e.g., Alzheimer’s and Parkinson’s diseases) to relatively moderate loss (e.g., progressive supranuclear palsy). Recently, a cluster of neuropathological and functional discoveries has evidenced the relevant role of the olfactory bulb (OB) during the neurodegenerative process. For instance, the double-transgenic APP/PS1 mouse model of Alzheimer’s disease (AD) develops early proteomic disturbances accompanied by a specific modulation of the focal adhesion kinase (FAK) and mitogen-ac-tivated protein kinase (MAPK) dynamics at the level of the OB, demonstrating that olfactory molecular alterations occur prior to β-amyloid plaque appearance and memory impairments in APP/ PS1 transgenic mice. Nevertheless, there are currently specific questions which should be addressed in human neurodegeneration: Does the loss of smell precede the onset of ND-specific neuropathological features? What is the metabolic impairment induced by protein inclusions in the OB? Is it disease-specific or tauopathy/synucleinopathy-dependent? How the neuropathological substrates modulate their constitutive interactome at olfactory level? Are there common olfactory targets across different neurological backgrounds?