Objective: To investigate how amyloid-beta (Aβ) pathology affects α-synuclein (α-syn) propagation.

Background: Lewy bodies, the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, are intraneuronal inclusion bodies rich in α-syn. Braak et al. proposed that Lewy body pathology spreads along neuronal connection, initially developing in the olfactory bulb (OB) and the lower brainstem, called Braak hypothesis. Prion-like propagation of α-syn has been increasingly recognized as the mechanism underlying Braak hypothesis. Based on this mechanism, α-syn preformed fibril (PFFs) injection into the unilateral OB of wild-type (WT) mice displayed sequential α-syn propagation along anatomical connections. However, these mice exhibited no motor or anxiety-related deficits or significant pathological findings in the cortical areas. In this study, we hypothesized that Aβ pathology may act as an additional factor in the progression of α-syn pathology in Lewy body disease (LBD), because more than 50% of patients exhibit coexisting Aβ pathology.

Method: α-syn PFFs or phosphate-buffered saline(PBS) were injected into the bilateral OB of amyloid precursor protein knock-in mice (APP^{NL-G-F/NL-G-F}) and WT mice at 4 months of age (n=4). Histological examinations were performed 3 months after the injection.

Results: APP^{NL-G-F/NL-G-F} mice exhibited abundant propagation of α-syn in widespread brain regions, including the anterior olfactory nucleus, amygdala, hippocampus, dentate gyrus, caudate-putamen, and frontal cortex compared to WT mice. No clear differences were observed in Aβ pathology between PFF- and PBS-injected APP^{NL-G-F/NL-G-F} mice.

Conclusion: Coexistence of Aβ pathology promotes the propagation of α-syn and may play an important role in the pathophysiology of Parkinson’s disease with dementia and dementia with Lewy bodies.

References: [1] Nolwen L. Rey, Sonia George, Jennifer A. Steiner, Zachary Madaj, Kelvin C. Luk, John Q. Trojanowski, Virginia M.Y. Lee, Patrik Brundin (2018) Spread of aggregates after OB injection of α‑synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathologica 135:65–83

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-a%ce%b2-on-%ce%b1-synuclein-propagation/