Syk and Yea Shall Find

The article by Ghosh and Ghealen in the current issue of Syk in AD are poorly understood. In addition, little is known about EBioMedicine provides new insights into the pathophysiology of the inflammatory system in Alzheimer's disease (AD). The story describing the accumulation of aggregated proteins in the AD brain, including β-amyloid and tau protein, has been developing since Alois Alzheimer first identified neurofibrillary tangles with a silver stain more than 100 years ago. Classically, neuritic plaques composed of aggregated Aβ peptides accumulate in the neuropil, outside neurons and glia, while neurofibrillary tangles composed of aggregated tau accumulate within neurons. The localization of these proteins necessarily focused attention on neuronal dysfunction in AD. However, all neurodegenerative diseases also suffer from a dysfunctional inflammatory response, but the biological basis of this response is largely unknown. The classic model for the inflammatory response posits the presence of two states:M1, a cytotoxic state, andM2, a regenerative state. This simplemodel describingM1 andM2 in ADwas initially appealing but now appears to insufficiently describe the varied immunological states characteristic of the AD brain. This model appears to be inadequate because it omits the process of phagocytosis, which appears to play a very important role in AD. Recent Genome-wideAssociation Studies have implicated triggering receptor expressed on myeloid cells 2 (TREM2) and CD33, both of which regulate microglial phagocytosis, in AD. The signaling pathway leading from TREM2 plays a key role in the article by Ghosh and Ghealan. TREM2 couples to TYRO protein tyrosine kinase binding protein (TYROBP), which then recruits spleen tyrosine kinase (Syk) to the phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) of TYROBP, and activates phagocytosis (N'Diaye et al., 2009). CD33 is also a risk factor for AD, but acts in opposition to TREM2. CD33 binds to Syk through its immunoreceptor tyrosine-based inhibitory motif (ITIM) domain and inactivate the phagocytic response of microglia. These studies suggest that TREM2 and CD33 play important reciprocal roles in regulating the phagocytic function of microglia in the CNS, with Syk acting as a downstream kinase that mediates the actions of TREM2 and CD33 on phagocytosis. However the actions of