Work

Neuroinflammation is an early pathological process in a mouse model of prodromal Parkinson’s disease

Year: 2026

Type: preprint

Abstract: Approximately 90% of Parkinson’s disease (PD) patients exhibit olfactory deficits, which often precedes motor symptoms by years, and are a robust predictor for PD and subsequent cognitive decline. Pathological changes in the PD olfactory system, particularly α-synuclein (αSyn) pathology in the olfactory bulb (OB) and severe involvement of the anterior olfactory nucleus (AON), are distinct from normal aging. However, the causal link between αSyn aggregation and functional impairment, potentially involving cytotoxicity and neuroinflammation, remains elusive. To investigate these early pathological events, we utilized a prodromal PD model that we have previously characterized, involving the unilateral OB injection of αSyn pre-formed fibrils (PFF) in wild-type mice. This triggers the transneuronal spread of pathogenic αSyn, and olfactory dysfunction starting at 1-month post-injections. Here we report on neuropathological and inflammatory events 1–3 month following injection of PFFs into the OB. Following PFF injection, αSyn pSer129 pathology progressively accumulated bilaterally in the AON and ipsilateral in the piriform cortex (PCX) over three months. Stereological quantification revealed no significant neuronal loss in the AON or PCX during this 1–3 month interval, indicating that olfactory impairment precedes overt neurodegeneration. Instead, we identified the upregulation of pro-inflammatory genes ( Il- 1β and Il-6 ), significant microglial reactivity, and sustained astrogliosis within olfactory structures. These findings identify neuroinflammation as a key early mediator linking αSyn pathology to olfactory dysfunction in the absence of neuronal loss. This suggests a critical window for therapeutic intervention and highlights neuroinflammatory markers as potential biomarkers for the prodromal phase of PD. Highlights Neuroinflammation Precedes Neuron Loss. Inflammation is an early pathological process that is detected before any significant loss of NeuN-positive neurons in olfactory structures. Progressive αSyn pSer129 spreading. Pathological αSyn pSer129 progressively spreads transneuronally from the injection site in the OB to secondary olfactory structures (AON and PCX) within 1 to 3 months. Early Microglial Reactivity. The spreading of αSyn pSer129 pathology rapidly induces microglial reactivity, which is prominent at the 1- and 2-month time points. Persistent Astrogliosis. Astrogliosis is also an early and persistent component of the neuroinflammatory response, starting at 1 month and remaining detectable through 3 months, suggesting a sustained inflammatory environment.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.29.762888