title: IL12/23 p40 inhibition ameliorates Alzheimer's disease-associated neuropathology and spatial memory in SAMP8 mice.
abstract: 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.
authors.affiliation: College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China.
authors.forename: Meng-Shan
authors.initials: MS
authors.lastname: Tan
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Yu
authors.forename: Teng
authors.initials: T
authors.lastname: Jiang
authors.forename: Xi-Chen
authors.initials: XC
authors.lastname: Zhu
authors.forename: Hua-Shi
authors.initials: HS
authors.lastname: Guan
authors.forename: Lan
authors.initials: L
authors.lastname: Tan
mesh_terms: D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D016708:Synaptophysin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D053762:Interleukin-12 Subunit p40; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016708:Synaptophysin; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Aging; Alzheimer's disease; IL-12; IL-23; SAMP8; amyloid-β; memory impairment