Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain

Abstract

Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections’ putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB.

In vivo bioluminescence imaging of the intracerebral fibroin-controlled AAV-α-synuclein diffusion for monitoring the central nervous system and peripheral expression

“…Besides the inadequacy of the present model (that models the overexpression of monomeric synuclein seen in familial PD with duplication, triplication or quadruplication of the SNCA gene 33 ), the question remains. Mixing α-syn preformed fibrils 34 , 35 or PD patients’ brain extracts 36 – 38 with an AAV-nanoluc (or directly with small amounts of nanoluc itself) should be tested to hopefully indirectly image aggregates in the living animal brain.…”

Nigral ATP13A2 depletion induces Parkinson's disease-related neurodegeneration in non-human primates

“…Hence, the importance of the Gardner-Altman plots that focus upon the effect size of the difference, when any. Many studies conducted by our team and other colleagues working on NHPs have generally used these types of low group sizes [47][48][49][50][51][52][53][54][55][56][57] . Our team is, however, known to involve a much larger number of NHPs when moving to de nitive studies 41,[58][59][60][61] that have always con rmed experiments with lower n.…”