Objective: We investigated how α-synuclein (α-Syn) pathology spreads from the olfactory bulb (OB) and how the pathology affects brain structure and activity.

Background: Parkinson’s disease (PD) is a neurodegenerative disease characterized byα-Syn aggregates. The α-Syn aggregates are believed to propagate in the brain like prion via two major pathways: the olfactory and vagal nerve pathways. Recently the common marmoset (Callithrix jacchus), a new world monkey, has gathered a lot of attention in the field of neuroscience because of its useful characteristics as a non-human primate model (NHP).

Method: Recombinant full-length marmoset α-Syn was purified and incubated with agitation for a week to generate α-Syn fibrils. Four two-year-old marmosets were anesthetized, and 0.8 ul of fibrils solution (4 mg/ml) was stereotaxically injected at two sites in the unilateral OB. Three or six months after the injection, the marmosets were measured regional brain structure and activity by manganese-enhanced MRI (MEMRI) and [¹⁸F]FDG-PET, and then sacrificed. The brains were fixed with 4% PFA in PBS and sliced into 8 μm coronal sections which were immunostained by anti-phosphorylated α-Syn (p-α-Syn), anti-ubiquitin (Ub) and anti-p62 antibodies.

Results: Widespread distribution of p-α-Syn positive aggregation was observed in the ipsilateral OB, amygdala, entorhinal cortex, locus coeruleus and even dorsal motor nucleus suggesting the spreading of α-Syn pathology along with anatomically connected neurons. These p-α-Syn positive aggregations were also positive for Ub and p62. MEMRI showed that marmoset injected with α-Syn fibrils developed the atrophy of OB and frontal lobe. In addition, [¹⁸F]FDG-PET study revealed widespread hypometabolism beyond pathologically affected brain regions. Glucose hypometabolism in several cortical areas are reported to be a predictive marker for development of cognitive dysfunction in patients with PD.

Conclusion: The OB atrophy and hemispheric hypoactivity in this NPH PD model might be associated with hyposmia and cognitive dysfunction, both of which are non-motor symptoms of PD. This study demonstrated that these symptoms are presumably attributed to the spread of α-Syn pathology from the OB.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/%ce%b1-synuclein-propagation-via-olfactory-pathway-induces-olfactory-bulb-atrophy-and-widespread-glucose-hypometabolism-in-a-non-human-primate-model/