TYK2 inhibition reverses immune-mediated neural cell death triggered by cytoplasmic dsRNA, a damage associated molecular pattern present in Alzheimer’s Disease

ABSTRACT: Neuroinflammation is a pathological feature of distinct neurodegenerative diseases, including Alzheimer’s disease (AD) and ALS, raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS. CdsRNA triggers a type-I interferon-based innate immune response in human neural cells, resulting in their death. The relevance of cdsRNA in other neurodegenerative diseases remains elusive. Up to 50% of brains with Alzheimer’s Disease pathology harbor cytoplasmic pTDP-43 aggregation. Here, we report a striking pathological similarity to ALS by demonstrating that cdsRNA is spatially coincident with pTDP-43 inclusions in brain cells of patients with AD. Consistent with this finding, the analysis of AD patient RNA-seq data further showed that type-I interferon signaling is significantly increased in brain regions relevant in AD. Cytoplasmic inclusions of TDP-43 may confer nuclear hypofunction of TDP-43, which increases expression of cryptic exons in STMN2 and UNC13A. We modified our machine-learning drug repurposing predictor pipeline DRIAD (Drug Repurposing In Alzheimer’s Disease) to incorporate cryptic exon detection as a proxy of pTDP-43 inclusions. Baricitinib and ruxolitinib – FDA-approved JAK inhibitors that block interferon signaling – showed a protective signal in cryptic exon expressing brain regions but not in AD patients without cryptic exons. These results confirm that targeting JAK-mediated immune responses are not only a target in ALS but also in a cdsRNA/pTDP-43-positive subset of AD. In an in-vitro model of cdsRNA-mediated death in differentiated human neural cells lacking microglia, we conducted a CRISPR-screen. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive CSF biomarkers for neurodegenerative diseases with an underlying dsRNA-related neuroimmune pathology. Together our findings reveal parallel mechanisms and therapeutic responses for thus far incurable neurodegenerative diseases, affording the possibility to study a therapeutic approach for more than one disease in the Neurodegenerative AD and ALS (NADALS) basket clinical trial (NCT05189106) which is an open label proof of concept clinical trial of baricitinib in patients along the Alzheimer’s and ALS disease spectrum with elevated CSF biomarkers of neuroinflammation responsive to baricitinib in model systems. Read less

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Gary Bradshaw  

LAB HEAD: Mark Albers

PROVIDER: PXD043641 | Pride | 2025-12-09

REPOSITORIES: Pride