Neuronal TNFα, Not α-Syn, Underlies PDD-Like Disease Progression in IFNβ-KO Mice

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Parkinson's disease (PD) and Parkinson's disease dementia (PDD) involve motor and non-motor symptoms, with hallmarks of neurodegeneration, Lewy bodies (LBs), and neuroinflammation.
• Alpha-synuclein (α-syn) aggregation is central to PD, but its role in sporadic PDD, especially when comorbid with amyloid-beta (Aβ) and phosphorylated tau (pTau), remains unclear.

Purpose of the Study:

• To investigate the role of alpha-synuclein (α-syn) in Parkinson's disease dementia (PDD) pathogenesis.
• To determine if the absence of α-syn influences PDD manifestation and neuropathology.

Main Methods:

• Generated and analyzed interferon-beta (IFN-β) and Snca double knockout (DKO) mice, comparing them to wild-type, Ifnb single knockout, and Snca single knockout mice.
• Utilized immunohistochemistry, electron microscopy, immunoblots, and qPCR to assess behavioral and neuropathological changes.

Main Results:

• IFN-β loss alone, independent of α-syn, induced PDD-like behaviors, Aβ plaques, pTau tangles, LB-like inclusions, and neuroinflammation.
• IFN-β deficiency elevated TNF-α and TNFR1, leading to neurodegeneration via caspase 3/t-BID activation.
• Restoring IFN-β signaling or blocking TNFR1 rescued neuronal death and reduced Aβ and pTau accumulation.

Conclusions:

• Alpha-synuclein is not the sole driver of neurodegeneration in sporadic PDD; IFN-β loss plays a critical role.
• Targeting neuroinflammation, specifically aberrant neuronal TNF-α/TNFR1 or IFN-β/IFNAR signaling, presents a potential therapeutic avenue for PDD.