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

Area of Science:

• Neuroscience
• Pathology
• Primate Models

Background:

• Synucleinopathies, including Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB), are defined by aggregated alpha-synuclein (α-syn) forming Lewy Bodies (LBs).
• Previous research showed patient-derived LB fractions induce pathology in primate nigrostriatal and enteric systems.
• The cortical impact of LB injection and subsequent pathology propagation remains less understood.

Purpose of the Study:

• To investigate the pathological consequences of injecting PD patient-derived LB fractions into the non-human primate prefrontal cortex.
• To assess α-syn pathology spread, neuronal survival, and impact on the nigrostriatal system.
• To evaluate the potential of this model for studying DLB pathology.

Main Methods:

• Mesencephalic PD patient-derived LB fractions were injected into the prefrontal cortex of baboon monkeys.
• Analyses included assessing phosphorylated α-syn (pSyn) at S129, quantifying neuronal, microglial, and astrocytic cells.
• The integrity of the nigrostriatal system was evaluated one year post-injection.

Main Results:

• pSyn accumulation was observed in the prefrontal cortex, connected cortical regions, and the striatum, indicating pathological propagation.
• Neuronal loss occurred in the prefrontal cortex and caudate nucleus.
• No loss of nigral dopamine neurons was detected, but pathology spread to connected areas.

Conclusions:

• Patient-derived LB extracts are toxic and can propagate pathology from the cortex to the striatum in non-human primates.
• This study establishes a potential primate model for Dementia with Lewy Bodies.
• Further research is needed to fully elucidate the mechanisms and implications of cortical LB pathology.