Abstract
Neurodegenerative disorders such as Parkinson’s Disease (PD), PD dementia (PDD) and Dementia with Lewy bodies (DLB) are characterized by progressive accumulation of α-synuclein (α-syn) in neurons. Recent studies have proposed that neuron-to-neuron propagation of α-syn plays a role in the pathogenesis of these disorders. We have previously shown that antibodies against the C-terminus of α-syn reduce the intra-neuronal accumulation of α-syn and related deficits in transgenic models of synucleinopathy, probably by abrogating the axonal transport and accumulation of α-syn in in vivo models. Here, we assessed the effect of passive immunization against α-syn in a new mouse model of axonal transport and accumulation of α-syn. For these purpose, non-transgenic, α-syn knock-out and mThy1-α-syn tg (line 61) mice received unilateral intra-cerebral injections with a lentiviral (LV)-α-syn vector construct followed by systemic administration of the monoclonal antibody 1H7 (recognizes amino acids 91-99) or control IgG for 3 months. Cerebral α-syn accumulation and axonopathy was assessed by immunohistochemistry and effects on behavior were assessed by Morris water maze. Unilateral LV-α-syn injection resulted in axonal propagation of α-syn in the contra-lateral site with subsequent behavioral deficits and axonal degeneration. Passive immunization with 1H7 antibody reduced the axonal accumulation of α-syn in the contra-lateral side and ameliorated the behavioral deficits. Together this study supports the notion that immunotherapy might improve the deficits in models of synucleinopathy by reducing the axonal propagation and accumulation of α-syn. This represents a potential new mode of action through which α-syn immunization might work.
Highlights
Synucleinopathies affect over 1 million people in the US alone [49]
Results α-Syn transmits and accumulates in axons in the contralateral side following unilateral LV-α-syn injection into the hippocampus To evaluate if antibodies against α-syn can reduce axonal transport and accumulation of α-syn in the contralateral side, we first developed a new animal model of neuronal α-syn transmission utilizing unilateral intra-hippocampal injections of LV-control or LV-α-syn into α-syn-KO, non-tg and α-syn tg mice (Fig. 1)
Since α-syn KO, non-tg, and α-syn tg mice injected with the LV-control did not show detectable increases in α-syn immunoreactivity in the ipsilateral or contralateral sides when compared to non-injected controls (Fig. 2a, f ), all ensuing experiments focused on alterations in α-syn KO, non-tg, and α-syn tg mice injected with LV-α-syn
Summary
Synucleinopathies affect over 1 million people in the US alone [49]. This heterogeneous group of disorders includes idiopathic Parkinson’s disease (PD), PD dementia (PDD) and dementia with Lewy bodies (DLB) [48]. This, in combination with recent studies showing that α-syn oligomers can be released by neurons and promote neurodegeneration and inflammation by propagating to other neurons [8, 12, 20, 37, 50] and glial cells [35], has strengthened the concept that cell-to-cell transmission of pathogenic forms of α-syn might play a role in the pathogenesis of synucleinopathies. Supporting the later hypothesis, recent studies have shown that injections of α-syn with viral vectors into the nucleus of vagus [22] or fibrils into the olfactory bulb [38, 47, 55, 56], striatum or limbic system [38] results in α-syn distribution along axons and synapses following known patterns of synaptic connectivity
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