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

Objective Parkinson's disease (PD) manifests in motor dysfunction, non‐motor symptoms, and eventual dementia (PDD). Neuropathological hallmarks include nigrostriatal neurodegeneration, Lewy body (LB) pathology, and neuroinflammation. Alpha‐synuclein (α‐syn), a primary component of LBs, is implicated in PD pathogenesis, accumulating, and aggregating in both familial and sporadic PD. However, as α‐syn pathology is often comorbid with amyloid‐beta (Aβ) plaques and phosphorylated tau (pTau) tangles in PDD, it is still unclear whether α‐syn is the primary cause of neurodegeneration in sporadic PDD. We aimed to determine how the absence of α‐syn would affect PDD manifestation. Methods IFN‐β knockout ( Ifnb −/− ) mice spontaneously develop progressive behavior abnormalities and neuropathology resembling PDD, notably with α‐syn + LBs. We generated Ifnb/Snca double knockout (DKO) mice and evaluated their behavior and neuropathology compared with wild‐type (Wt), Ifnb −/− , and Snca −/− mice using immunohistochemistry, electron microscopy, immunoblots, qPCR, and modification of neuronal signaling. Results Ifnb/Snca DKO mice developed all clinical PDD‐like behavioral manifestations induced by IFN‐β loss. Independently of α‐syn expression, lack of IFN‐β alone induced Aβ plaques, pTau tangles, and LB‐like Aβ + /pTau + inclusion bodies and neuroinflammation. IFN‐β loss caused significant elevated glial and neuronal TNF‐α and neuronal TNFR1, associated with neurodegeneration. Restoring neuronal IFN‐β signaling or blocking TNFR1 rescued caspase 3/t‐BID‐mediated neuronal‐death through upregulation of c‐FLIP S and lowered intraneuronal Aβ and pTau accumulation. Interpretation These findings increase our understanding of PD pathology and suggest that targeting α‐syn alone is not sufficient to mitigate disease. Targeting specific aspects of neuroinflammation, such as aberrant neuronal TNF‐α/TNFR1 or IFN‐β/IFNAR signaling, may attenuate disease. ANN NEUROL 2021;90:789–807