It is likely that innate immune activation can have positive or negative effects on proteostasis and behavioral and neurodegenerative phenotypes. That balance between positive and negative effects would contextually depend on the nature, timing, duration, and strength of the specific signals. This manuscript adds, in a very intriguing way, to the conflicting data on the relationship between altered innate immune activation states (“pro” or “anti”-inflammatory) and their effects on extracellular Aβ accumulation. At the end of the day, it is likely we will find that these manipulations have more complex effects on Aβ metabolism and other phenotypes than those currently being surveyed, and that a simple dichotomy of M1 versus M2 microglial phenotypes will not be sufficient to explain all results.

Indeed, trying to find mechanisms in these types of studies is challenging; in this regard, the authors do not look at steady-state Aβ levels in pre-young mice without Aβ deposits. That would be key to ascertain whether other effects that alter Aβ levels might be at play.

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