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Posts Tagged ‘Interleukin 12’


Curator: Aviva Lev-Ari, PhD, RN

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

  1. These authors contributed equally to this work.

    • Johannes vom Berg &
    • Stefan Prokop

Affiliations

  1. Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.

    • Johannes vom Berg,
    • Florian Mair &
    • Burkhard Becher
  2. Department of Neuropathology, Charité–Universitätsmedizin Berlin, Berlin, Germany.

    • Stefan Prokop,
    • Kelly R Miller,
    • Juliane Obst,
    • Roland E Kälin,
    • Ileana Lopategui-Cabezas,
    • Anja Wegner,
    • Carola G Schipke &
    • Frank L Heppner
  3. Department of Psychiatry, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

    • Carola G Schipke &
    • Oliver Peters
  4. Cognitive Neurobiology and Berlin Mouse Clinic for Neurology and Psychiatry, Humboldt University, Berlin, Germany.

    • York Winter
  5. Present address: Institute of Basic and Preclinical Sciences ‘Victoria de Girón’, Medical University of Havana, Havana, Cuba.

    • Ileana Lopategui-Cabezas
  6. These authors jointly directed this work.
    • Burkhard Becher &
    • Frank L Heppner

     

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 (). Using theAPPPS1 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.

Nature Medicine 18, 1812–1819 (2012) doi:10.1038/nm.2965, Published online 25 November 2012

Psoriasis Drug Fights Alzheimer’s By Treating It Like An Auto-Immune Disease

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In a study published this week in the journal Nature Medicine, Swedish and German researchers say a medication already widely in use to treat plaque psoriasis was able to slow the accumuation of amyloid plaques in the brains of mice, as well as improve brain functioning in older mice that already had Alzheimer’s disease.

The drug, ustekinumab, works by suppressing the brain’s immune response to the amyloid-beta protein. Its effectiveness lends support to the idea of Alzheimer’s disease as an auto-immune disease similar to type-2 diabetes, spurred at least in part by the bodies response to inflammation.

The study authors urged the U.S. Food & Drug Administration should approve ustekinumab for patients with early Alzheimer’s disease or mild cognitive impairment and said drugs that shut down specific immune responses — like those used in psoriasis, Crohn’s disease and multiple sclerosis — are “the ideal candidate for the initiation of clinical trials” for Alzheimer’s.

That’s very good news, because pharmaceutical companies have been ready to give up on Alzheimer’s drug development after so many of the drugs being tested for the past decade or more have been failures. Most of those drugs worked under different theories of treating Alzheimer’s disease, focusing more on things like busting up existing plaques or treating the external symptoms of Alzheimer’s.

http://www.blisstree.com/2012/11/28/sex-relationships/psoriasis-drug-fights-alzheimers-by-treating-it-like-an-auto-immune-disease/#ixzz2M7ceuApw

Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

W. Sue T. Griffin, Ph.D.

N Engl J Med 2013; 368:770-771 February 21, 2013, DOI: 10.1056/NEJMcibr1214546

Immune events may influence development and progression of Alzheimer’s disease. In a mouse model, mice depleted of p40, a cytokine subunit, showed reduced cerebral amyloidosis. Administration of anti-p40 antibodies reduced levels of soluble β-amyloid and restored some cognitive function.

Neuroinflammation, expressed as frank microglial activation with excessive expression of immune cytokines, is fast acquiring the status of “principal culprit” in the unresolved connection between an elevated risk for the development of

  • sporadic Alzheimer’s disease and
  • traumatic brain injury,
  • systemic infections,
  • normal aging, and
  • several neurologic disorders.

Neuroinflammation also appears to be a substantial contributor to Alzheimer’s disease in persons with Down’s syndrome (owing to the excess gene dosage that is characteristic of the syndrome) and in persons with genetic mutations that affect the amyloid precursor protein (APP) or presenilin.1 The molecules and pathways that mediate the inflammation associated with Alzheimer’s disease have recently come under scrutiny. An advance in this area has been described by Vom Berg et al.,2 who used a mouse model of Alzheimer’s disease to investigate the role of proinflammatory cytokines in disease pathogenesis.

Their results show that damping the expression and signaling of the cytokines interleukin-12 and interleukin-23 in the mouse model is associated with decreases in microglial activation, in the level of soluble β-amyloid (Aβ), and in the overall Aβ plaque burden. These findings are consistent with earlier studies that linked microglial activation with excess expression of interleukin-1 (which regulates interleukin-12–interleukin-23 signaling3) and expression of APP (which when cleaved generates Aβ), the development of Aβ plaques, and the activation of microglia in the brains of patients with Alzheimer’s disease.

Vom Berg et al. also observed that intracerebroventricular delivery of an antibody against p40 — a subunit common to both interleukin-12 and interleukin-23 — reversed the age-related cognitive decline in mice and that this reversal was accompanied by a reduction in levels of soluble Aβ. These observations suggest that the suppression of signaling by interleukin-12, interleukin- 23, or other inflammatory cytokines may prevent or delay the onset of Alzheimer’s disease and, for patients already undergoing the cognitive decline of Alzheimer’s disease, may halt such decline. 

These findings raise the question of whether monoclonal p40 antibodies (ustekinumab and briakinumab), which have already been approved by the Food and Drug Administration for the treatment of psoriasis, should be tested in randomized, controlled trials for the treatment of Alzheimer’s disease. Also of interest is a large epidemiologic study4 in which the rate of incident Alzheimer’s disease decreased by almost 50% among persons who took the common nonsteroidal antiinflammatory agent (NSAID) ibuprofen for 5 years, a finding that suggests that experimental investigation of NSAIDs as preventive agents is warranted.

Given the mounting sociological, economic, and personal costs of Alzheimer’s disease, the lack of a perfect understanding of its mechanisms should not stop researchers from conducting clinical studies of a variety of strategies intended to reduce the risk of development of the disease and of experimental approaches to expedite its treatment.

W. Sue T. Griffin, Ph.D.: Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Donald W. Reynolds Department of Geriatrics and Institute on Aging, University of Arkansas for Medical Sciences, and the Geriatric Research, Education, and Clinical Center (GRECC) at the Central Arkansas Veterans Healthcare System — both in Little Rock.

1. Griffin WS, Barger SW. Neuroinflammatory cytokines — the common thread in Alzheimer’s pathogenesis. US Neurol 2010; 6(2):19-27.

2. Vom Berg J, Prokop S, Miller KR, et al. Inhibition of IL-12/ IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 2012;18:1812-9.

3. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000;13: 715-25.

4. Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 2008;70:1672-7.

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