Neuroinflammatory Cytokine Signaling and Alzheimer's Disease
W. Sue T. Griffin, Ph.D.
N Engl J Med 2013; 368:770-771
February 21, 2013
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 (Figure 1Figure 1
Inflammatory Events and Alzheimer's Disease.). 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.
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.