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.

The concept of alpha-synuclein as a prion-like protein: ten years after

“…Moreover, intracerebral injections of α-syn into the cortical areas results in pathological spreading from the cortex to the striatum, thalamus, hypothalamus, locus coeruleus, raphe nucleus, reticular formation, cerebellum, and the spinal cord (Luk et al 2012b; Mougenot et al 2012; Watts et al 2013). Being one of the main predicted entry sites for aggregated α-syn, the olfactory bulb may be quite critical for α-syn propagation (Rey et al 2016c). Indeed, olfactory bulb injections trigger the spread of aggregated α-syn in an anatomical pattern across several brain areas including the frontal, entorhinal, perirhinal, and parietal cortex, as well as the striatum, amygdala, substantia nigra, and hippocampus (Rey et al 2016b).…”

“…In what was suggested to be the earliest phases of the disease (Braak stage 1 and 2, which actually precede the onset of the classical motor symptoms), α-syn-immunopositive pathology was found in two distinct brain areas, the dorsal motor nucleus of the vagal nerve and the anterior olfactory nucleus. Therefore, the authors proposed that these locations might be initiation sites that direct the spread of the pathology stereotypically throughout the brain (reviewed in (Rey et al 2016c)). In the same timeframe, Hardy published a permissive templating theory regarding neurodegenerative diseases including Parkinson’s (Hardy 2005).…”

Alpha-Synuclein to the Rescue: Immune Cell Recruitment by Alpha-Synuclein during Gastrointestinal Infection

“…Due to the proposed triggering of an increase in neuronal and extracellular alpha-synuclein, infections with certain gut pathogens can constitute a risk factor for PD. A similar reasoning might apply to the olfactory system, which is exposed to numerous pathogens via the olfactory epithelium and is suggested to be one of the first sites of alpha-synuclein aggregation in PD [39]. This raises the possibility that PD is not the result of a select causative agent(s), but rather a failure in the systems in place that should protect against alpha-synuclein aggregation.…”

Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

“…A more recently developed type of model involves the injection of α‐synuclein fibrils into the brain, which triggers a protracted development of α‐synuclein aggregates in interconnected brain regions, followed by neurodegeneration in some of the affected brain regions (eg, loss of nigral dopamine neurons after injection of fibrils into the striatum) . An advantage with this last paradigm is that it is possible to mimic some of the neuropathology and functional deficits seen in prodromal PD by injecting the fibrils into the olfactory bulb …”