Interleukin-34 modulation of microglia in Alzheimer’s disease

Identification: Raposo, Catarina


Description

Interleukin-34 modulation of microglia in Alzheimer's disease
 
Catarina Raposo1,2, Iva Lelios2, Roland Schmucki1, Solveig Badillo1, Isabelle Wells1, Juerg Messer1, Melanie Greter2, Burkhard Becher2 and Irene Knuesel1
1Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel; 
2Institute of Experimental Immunology, University of Zurich
 
Microglia play central roles in CNS health and disease. Colony-stimulating factor receptor 1 (CSF1R) and its ligands, IL-34 and CSF1, are critical for microglia maintenance and homeostasis, positioning these molecules as good engagement targets for the development of immune-based therapeutics in neurodegenerative diseases such as Alzheimer's disease (AD). In particular, IL-34 is required for myeloid cells that populate the epidermis and CNS. As such, unlike CSF1R and CSF1, targeted deletion of IL-34 specifically affects microglia and Langerhans cells but not other myeloid populations, including blood monocytes, other tissue macrophages or dendritic cells. In addition, IL-34-/- mice demonstrate specific reductions in microglia in key brain areas affected in AD such as the hippocampus.
In a preclinical model for AD, we found that the loss of neuronal, homeostatic IL34 led to a dramatic change in the microglia gene signature, including increased Clec7a, Lgals3, Lpl, Cst7 and Apoe, a signature usually observed in AD-associated microglia. Of note, these markers were upregulated in the absence of pathology, suggesting that IL-34 may have an immunomodulatory role in microglia in addition to promoting microglia homeostasis. IL-34 starved microglia displayed increased phagocytosis of amyloid beta, which was reflected in reduced plaque coverage in the hippocampus and cortex of AD mice. Ongoing studies are underway to determine how the presence of such stressed microglia will affect disease progression. Given the importance of microglia in multiple neurodegenerative diseases, understanding how we can modulate its response will not only provide insights into the pathogenesis of CNS disorders, but may also generate novel targets for drug development and the optimization of existing therapies.
 

Credits

Credits: None available.

You must be logged in and own this product in order to post comments.