Type-1 interferons (IFN-1) are a pleiotropic group of cytokines initially known for their antiviral activity, but recent studies highlight a vital role of IFN-1 in central nervous system (CNS) homeostasis, brain aging, and neurodegeneration. Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with a complex etiology. The hallmark signs of AD that appear in the brain are amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Neuroinflammation facilitated primarily by microglia is known to drive amyloid and tau pathology, with evidence suggesting IFN-1 as a key player in AD pathogenesis. Activated microglia secrete IFN-1 in response to Aβ accumulation which activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) (JAK/STAT) pathway as well as the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS/STING) pathway, resulting in the expression of interferon-stimulated genes (ISGs). Implications of IFN-1 signaling during AD development include neuroinflammation, alterations in microglial morphology (microglial dysfunction), synapse/neuron loss, and cognitive impairment. Additionally, studies suggest blocking/attenuating the IFN-1 response results in reduced AD pathology and improved behavioral deficits. Here, we review the role of IFN-1 in AD pathogenesis. The ability to attenuate IFN-1, coupled with the well-established role of IFN-1 in AD pathogenesis, supports the notion that targeting this neuroinflammatory pathway may be a potential therapeutic strategy for AD.
Shippy et al. (Thu,) studied this question.