The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases

Abstract

Olfactory deficits are present in numerous neurodegenerative disorders and are accompanied by pathology in related brain regions. In several of these disorders, olfactory disturbances appear early and are considered as prodromal symptoms of the disease. In addition, pathological protein aggregates affect olfactory regions prior to other regions, suggesting that the olfactory system might be particularly vulnerable to neurodegenerative diseases. Exposed to the external environment, the olfactory epithelium and olfactory bulb allow pathogen and toxin penetration into the brain, a process that has been proposed to play a role in neurodegenerative diseases. Determining whether the olfactory bulb could be a starting point of pathology and of pathology spread is crucial to understanding how neurodegenerative diseases evolve. We argue that pathological changes following environmental insults contribute to the initiation of protein aggregation in the olfactory bulb, which then triggers the spread of the pathology within the brain by a templating mechanism in a prion-like manner. We review the evidence for the early involvement of olfactory structures in neurodegenerative diseases and the relationship between neuropathology and olfactory function. We discuss the vulnerability and putative underlying mechanisms by which pathology could be initiated in the olfactory bulb, from the entry of pathogens (promoted by increased permeability of the olfactory epithelium with aging or inflammation) to the sensitivity of the olfactory system to oxidative stress and inflammation. Finally, we review changes in protein expression and neural excitability triggered by pathogenic proteins that can promote pathogenesis in the olfactory bulb and beyond.

Keywords: Alpha-synuclein; Alzheimer's disease; Beta-amyloid; Neuroinflammation; Olfactory system; Parkinson's disease; Synucleinopathies; TDP-43; Tau; Tauopathies.

Fig. 1

Schematic of the olfactory mucosa and different defense mechanisms against pathogens entry and cellular damages by environmental exposure. 1) Bowman’s glands secrete the olfactory mucus that contains immune factors, lysozymes, enzymes, antioxidants, and possibly xenobiotic-metabolizing enzymes capable of viral inactivation, detoxification, bacterial degradation, and destruction of pro-inflammatory molecules. 2) The mucus layer in which cilia of olfactory receptor neurons (ORNs) are immersed provides electrical insulation to the neurons and catches particles and odorants in suspension in the air. 3) Sustentacular cells maintaining water and salt balance in the mucus and metabolize xenobiotics. 4) Dense network of tight junctions between sustentacular cells and ORNs, and between the serous cells of Bowman’s glands, prevent pathogens from infiltrating the olfactory epithelium (OE). 5) Sustentacular cells might phagocytose debris and dying cells. 6) Damaged ORNs are constantly replaced by newborn ORNs, differentiating from the globose cells that derive from the horizontal cells. 7) In case of damage to the OE or contamination, neutrophils and macrophages can invade the olfactory mucosa though the lamina propria. 8) Ensheathing cells protect and electrically isolate the axons of ORNs. 9) Nerve bundles are protected by fibroblasts enveloping them. 10) Microglial population localized in nerve bundles and in external layers of the olfactory bulb is believed to be in a contact state alert.