Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin-induced microglial activation

Identification: Song, Fei


Description

Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin-induced microglial activation
 
Fei Song, Jianguo Liu, and Jeffrey A. Loeb
Department of Neurology and Rehabilitation, University of Illinois at Chicago, IL 60612
Corresponding Author: Fei Song
 
There are no effective treatments to slow disease progression in ALS. We previously reported that neuregulin (NRG) receptors are constitutively activated on microglia in the ventral horns in both ALS patients and SOD1 mice and in the corticospinal tracts of ALS patients, and that NRG receptor activation occurs prior to significant clinical disease onset in SOD1 mice. Here, we hypothesize that blocking NRG signaling on microglia would slow disease progression in SOD1 mice using a targeted NRG antagonist (HBD-S-H4).  Recombinant HBD-S-H4 directly delivered into the central nervous system (CNS) through implanted intracerebroventricular cannulas showed no signs of toxicity and significantly inhibited NRG receptor activation on microglia resulting in reduced microglial activation and motor neuron loss. The treatment also resulted in a delay in disease onset and an increase in survival.  The therapeutic effect was dose-dependent that varied as a function of genetic background in two different strains of SOD1 mice.  As a complementary drug delivery approach, transgenic mice expressing HBD-S-H4 driven by an astrocytic promoter (GFAP) had slower disease progression in a dose dependent manner, based on the level of HBD-S-H4 expression. These studies provide mechanistic insights into how NRG signaling on microglia may lead to disease progression and demonstrate the utility of a humanized fusion protein that blocks NRG as a novel therapeutic for human ALS.
   
 

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