IL12/23 p40 inhibition ameliorates Alzheimer's disease-associated neuropathology and spatial memory in SAMP8 mice.

Progressively increased proinflammatory status is a major characteristic of the aging process and associated with age-related diseases such as Alzheimer's diseases (AD). However, the regulation and role of common proinflammatory cytokines, including interleukin-12 (IL-12) and IL-23, in the aged brain are still unclear. Using the senescence-accelerated mouse prone-8 (SAMP8) model, we screened the cerebral expression of IL-12/23 in 3-, 7-, and 11-month-old mice and observed that their levels in the brain were upregulated during aging. To further examine whether the heightened activation of inflammatory cytokines may contribute to age-related brain dysfunction, we employed direct in vivo infusion of nonviral small interfering RNA (siRNA) to knock down the common IL-12/23 signaling subunit p40 in the brain. We found that these p40-deficient mice had significantly decreased cerebral amyloid-β levels, reduced synaptic and neuronal loss, and reversed cognitive impairments. Furthermore, in vivo delivery of a neutralizing p40-specific antibody likewise ameliorated AD-associated pathology and cognitive deficits in SAMP8 mice. Thus, our data indicate that the upregulated cerebral IL-12/23 during aging is involved in age-associated brain dysfunction and point to the modulation of IL-12/23 signaling molecule p40 as a promising strategy for the development of an AD therapy.