Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early neuronal loss and is reduced long term

Abstract

Parkinson’s disease is characterized by degeneration of substantia nigra dopamine neurons and by intraneuronal aggregates, primarily composed of misfolded α-synuclein. The α-synuclein aggregates in Parkinson’s patients are suggested to first appear in the olfactory bulb and enteric nerves and then propagate, following a stereotypic pattern, via neural pathways to numerous regions across the brain. We recently demonstrated that after injection of either mouse or human α-synuclein fibrils into the olfactory bulb of wild-type mice, α-synuclein fibrils recruited endogenous α-synuclein into pathological aggregates that spread transneuronally to over 40 other brain regions and subregions, over 12 months. We previously reported the progressive spreading of α-synuclein aggregates, between 1 and 12 months following α-synuclein fibril injections, and now report how far the pathology has spread 18- and 23-month post-injection in this model. Our data show that between 12 and 18 months, there is a further increase in the number of brain regions exhibiting pathology after human, and to a lesser extent mouse, α-synuclein fibril injections. At both 18 and 23 months after injection of mouse and human α-synuclein fibrils, we observed a reduction in the density of α-synuclein aggregates in some brain regions compared to others at 12 months. At 23 months, no additional brain regions exhibited α-synuclein aggregates compared to earlier time points. In addition, we also demonstrate that the induced α-synucleinopathy triggered a significant early neuron loss in the anterior olfactory nucleus. By contrast, there was no loss of mitral neurons in the olfactory bulb, even at 18 month post-injection. We speculate that the lack of continued progression of α-synuclein pathology is due to compromise of the neural circuitry, consequential to neuron loss and possibly to the activation of proteolytic mechanisms in resilient neurons of wild-type mice that counterbalances the spread and seeding by degrading pathogenic α-synuclein.Electronic supplementary materialThe online version of this article (10.1007/s00401-017-1792-9) contains supplementary material, which is available to authorized users.

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

“…In the latter 21.5‐month‐old males, fibril infusions elicited mild loss of NeuN + neurons in the AON. In contrast, Rey and colleagues achieved severe cell loss in this structure 6 months after fibril infusions in the OB of young C57 mice , perhaps because of differences in fibril sonication protocols or mouse strain; they employed C57 mice, whereas we examined CD1 mice.…”

“…Pinto and colleagues reported that 40% of older adults with complete smell loss were dead within 5 years (compared to only 10% of older adults with intact smell perception), and that smell loss was linked to higher mortality rates than heart failure, stroke, cancer and diabetes . Rey et al did not report an increase in mortality from olfactory‐seeded α‐synucleinopathy, but their mice were 3 months old at the time of fibril injections . In the present study, animals injected at 3 months of age also did not exhibit an increase in mortality, whereas infusions in the 11‐month‐old mice only exerted significant lethal effects by 10.5 months post‐infusion.…”

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…After 12 months, pS129‐positive inclusions were detected throughout the brain in connected areas, including the SNpc. However, there was no further progression of Lewy body‐like pathology at 23 months when pS129 was propagation studied after injecting PFFs into the mouse gastric wall (Rey et al., ; Uemura et al., ). The study demonstrated formation of pS129‐positive aggregates in the dorsal motor nucleus of the vagus nerve, which could be prevented by vagotomy.…”

“…A similar model in rats and non‐human primates also only showed minor Lewy body‐like pathology in rats at 1 month, which was gone over time despite persistent pathology in the enteric nervous system. Nor was Lewy body‐like pathology (Rey et al., ; Uemura et al., ) detected in non‐human primates at 12 months, despite extensive spread of α‐synuclein pathology in the enteric nervous system (Manfredsson et al., ).…”

Antibodies against alpha‐synuclein: tools and therapies

“…It has also been suggested that the distinct sequence of clinical features in PDD and DLB may result from pathology originating at different predilection sites, with PD beginning in the motor regions of the brainstem and midbrain, perhaps subsequent to peripheral α‐synucleinopathy, and DLB originating in the olfactory bulb interconnected to cognitive regions of the limbic system and neocortex (Rey et al . ).…”