Propagated but Topologically Distributed Forebrain Neurons Expressing Alpha-Synuclein in Aged Macaques

Area of Science:

• Neuroscience
• Neurodegenerative Diseases
• Primate Models

Background:

• Parkinson's disease (PD) involves alpha-synuclein (α-syn) accumulation, forming Lewy bodies (LB) and causing cell death.
• The propagation patterns of α-syn pathology in the brain remain poorly understood.
• Synucleinopathies are a class of neurodegenerative disorders characterized by α-syn aggregation.

Purpose of the Study:

• To investigate the distribution and propagation patterns of α-syn-expressing neurons in the forebrain of aged macaques.
• To explore the potential of aged macaques as a presymptomatic model for PD and LB-related disorders.

Main Methods:

• Examined α-syn-positive neurons in the forebrain of aged macaques.
• Mapped the topological spread of α-syn pathology along midbrain dopamine pathways.
• Assessed dopamine transporter levels and dopamine levels in relevant brain regions.

Main Results:

• α-syn-positive neurons were observed to propagate topologically from the substantia nigra and ventral tegmental area.
• Age-dependent increases in α-syn-positive neurons were found in the striatum (nigrostriatal pathway) and nucleus accumbens (mesolimbic pathway).
• Specific gradients of α-syn pathology were identified in the substantia nigra and striatum, with compensatory dopamine transporter increases in the striatum.

Conclusions:

• Aged macaques exhibit α-syn pathology spread mirroring early PD progression via dopamine pathways.
• The absence of Lewy bodies and clinical symptoms suggests aged macaques are a valuable presymptomatic model.
• This model can aid in understanding early synucleinopathy development and testing interventions for PD and related disorders.