Our network-based integrative analysis not only highlighted the immune/microglia module as the molecular system most strongly associated with the pathophysiology of LOAD, but identified the key network regulators including TYROBP. In a separate in vitro study we have found that the microglia expressed TYROBP is directly involved in amyloid-β turnover and neuronal damage (unpublished results). Of interest, mutations in TYROBP or TREM2 cause Nasu-Hakola disease (Bianchin et al., 2010), a rare Mendelian disease characterized by bone reabsorption dysfunction and chronic inflammatory neurodegeneration leading to death in the fourth or fifth decade of life. The exact pathomechanism underlying Nasu-Hakola disease is still unclear, but it was hypothesized that failure of proper microglial clearance is causal for the lethal effect of neurodegeneration. Thus dysfunctional immune/microglia pathways might not be unique to LOAD. To test the generalization of this concept, we explored the connection of the immune/microglia module to Huntington disease (HD), another neurodegenerative disease. HD pathology, caused by expanded alleles of a variable stretch of trinucleotide (CAG) repeat length in HTT (The Huntington’s Disease Collaborative Research Group, 1993), features astrogliosis and neurodegeneration
