Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline

Abstract

The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.

Increased Serum Levels of Interleukin-18, -23 and -17 in Chinese Patients with Alzheimer's Disease

“…IL-23 and IL-12 share a common subunit (p40). Other studies showed that improved cognitive performance was seen after blocking p40 by antibody, and the loss of p40 had the greatest impact on the reduction of Aβ plaque burden in an AD mouse model [16,29]. IL-17 was significantly increased in the cerebrospinal fluid of individuals with AD and in the brain of an AD mouse model [30,31].…”

Mild Cognitive Impairment in Patients with Moderate to Severe Chronic Plaque Psoriasis

“…TNF-α antagonists and ustekinumab have been shown to improve symptoms of depression [44], but whether they could improve cognitive functions in patients with psoriasis has not been investigated. Indeed, it has recently been found that inhibition of the IL-12/IL-23 pathway may attenuate cerebral amyloidosis and cognitive deficits in a mouse model of Alzheimer's disease [45]. …”

Microglia inflict delayed brain injury after subarachnoid hemorrhage

“…While astroglia are of neuroectodermal origin, microglia (MG) rely on lineagecommitted precursors in the yolk sac and are considered the brain's residential immune cells [1,36,57]. Microglia have been discussed to play pivotal roles in CNS pathologies like Alzheimer's disease, autoimmune encephalomyelitis, traumatic brain injury and ischemic stroke [4,8,32,38], where microglia fulfill their pleiotropic roles as cells of the innate immune system, including antigen presentation, phagocytosis and production of a variety of cytokines and chemokines. They have furthermore been described to be attracted to and activated by a variety of toxic or inflammatory stimuli and have been shown to initiate gliotic scar formation via secretion of respective cytokines.…”