Session Time: 1:45pm-3:15pm
Location: Exhibit Hall C
Objective: To investigate the impact and temporal aspects of the neuronal loss in the LC neurons induced by alpha-synucleinopathy
Background: In the Braak staging model of Parkinson’s disease (PD), Lewy pathology progresses in a caudo-rostral pattern from the locus coeruleus (LC) to the substantia nigra (SN). The impact and temporal aspects of the neuronal loss in the LC neurons induced by alpha-synucleinopathy has neither been reported nor used as a prodromal animal model of PD.
Methods: We have performed a unilateral microinjection of recombinant adeno-associated viral vectors (rAAV) carrying human WT-aSYN, A53T-aSYN or luciferase as a control reporter in male C57Bl/6 mice. In total 1.25 μl volumes of rAAV vectors were delivered in the right hemisphere of the LC at coordinates (from dura) AP -5.4 mm, ML -0.9 mm, DV -3.7 mm. Eight animals in each group were sacrificed 3 weeks post the injection by a transcardial perfusion of PBS followed by ice-cold 4% paraformaldehyde. Immunohistochemistry for tyrosine hydroxylase (TH) for the LC and choline acetyltransferase (ChAT) for the medulla oblongata was performed to quantify neurons using stereological analysis.
Results: 3 weeks post aSYN overexpression we have found an approximate 16% neuronal loss of the LC in the injected hemisphere of rAAV WT-αSYN and A53T-αSYN compared to the non-injected side. The relative numbers of LC neurons in each hemisphere of WT-αSYN or A53T-αSYN group were significantly decreased when compared to that of rAAV-luciferase injected. In addition, we discovered that the number of ChAT positive neurons in the rostral nucleus ambiguus also significantly decreased in both rAAV WT-αSYN and A53T-αSYN injected animals, when compared to that of rAAV-luciferase injected.
Conclusions: rAAV WT-αSYN or A53T-αSYN overexpression in the LC caused a significant neuronal loss in the LC as early as 3 weeks post injection. Moreover, αSYN seems to play a role in the cell viability of neurons in the nucleus ambiguus. This result may imply a potential direct or indirect role of noradrenergic neurons in modulating motor innervation of the upper gastrointestinal system.
To cite this abstract in AMA style:B. Lee, M. Henrich, W.-H. Chiu, L. Matschke. AAV-mediated human alpha synuclein overexpression in the locus coeruleus (LC) leads to a neuronal loss in the nucleus ambiguus of mouse. [abstract]. Mov Disord. 2017; 32 (suppl 2). https://www.mdsabstracts.org/abstract/aav-mediated-human-alpha-synuclein-overexpression-in-the-locus-coeruleus-lc-leads-to-a-neuronal-loss-in-the-nucleus-ambiguus-of-mouse/. Accessed December 11, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/aav-mediated-human-alpha-synuclein-overexpression-in-the-locus-coeruleus-lc-leads-to-a-neuronal-loss-in-the-nucleus-ambiguus-of-mouse/