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Dec 20, 2012
 |  BC Innovations  |  Targets & Mechanisms

Targeting interleukins in Alzheimer's disease

Researchers at Charité-University Hospital Berlin and the University of Zurich have data showing that p40, a protein subunit shared by IL-12 and IL-23, could be a new therapeutic target in Alzheimer's disease.1 The group now is trying to better understand the downstream mediators of the pathway and wants to find an industry partner to test late-stage or marketed p40-targeting therapies, such as Johnson & Johnson's psoriasis drug Stelara ustekinumab.

p40 is produced by microglia and is a protein subunit shared by IL-12 and IL-23. Microglia are the resident macrophages of the CNS, and aberrant phenotypes are linked to multiple neurodegenerative diseases, including Alzheimer's disease (AD).2 These CNS cells accumulate around b-amyloid (Ab) plaques and are known to be a major source of proinflammatory cytokines,3 although their precise role in AD pathogenesis and progression is unclear.4

Ab plaques are hallmarks of AD and trigger inflammatory responses.5

A research group co-led by Frank Heppner has been trying to characterize the role of microglia in Ab pathology in AD. Initially, it seemed there was at least no immediate role. In 2009, his group reported that ablation of the microglia cell population for four weeks had no observable effect on Ab plaque load and amyloid-associated neurotoxicity in two mouse models of AD.6

Now, however, his team has shown that targeting a cytokine subunit produced by aberrant microglia for at least 60 days reduces Ab plaque loads and reverses AD pathology.

In a transgenic mouse model of AD, microglial production of p40-as well as levels of Il-12 and Il-23-was greater than that in wild-type controls.

"We found that these molecules were upregulated in a distinct subpopulation of microglia in this mouse model of Alzheimer's and thus thought they may be associated with disease pathology," said Heppner, chair of the Department of Neuropathology at Charité-University Hospital Berlin. "Thus, we sought to...

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