In this study, the authors have found that TGF-β signaling inhibits the natural properties of macrophages to clear Aβ and infiltrate the CNS of APP mice. Knocking out such signaling events was found to improve both the brain infiltration of bone marrow-derived macrophages/microglia and their clearance of Aβ, which prevented the cognitive decline in mouse models of AD.

These data fit very well with the novel concept that systemic innate immune cells have the capacity to fight against toxic proteins but do not do it in an efficient manner. That's probably because of anti-inflammatory signals (e.g., TGF-β), as elegantly demonstrated by Town and colleagues.

We recently reported that Toll-like receptor 2 gene deletion is also associated with Aβ42 accumulation and cognitive impairment, while TLR2 gene expression in bone marrow-derived cells rescued such a memory deficit (Richard et al., 2008). Of great interest here is that APPtg/TLR2 knockout mice had a spontaneous increase in TGF-β gene expression in immune cells adjacent to...  Read more

In this study, the authors have found that TGF-β signaling inhibits the natural properties of macrophages to clear Aβ and infiltrate the CNS of APP mice. Knocking out such signaling events was found to improve both the brain infiltration of bone marrow-derived macrophages/microglia and their clearance of Aβ, which prevented the cognitive decline in mouse models of AD.

These data fit very well with the novel concept that systemic innate immune cells have the capacity to fight against toxic proteins but do not do it in an efficient manner. That's probably because of anti-inflammatory signals (e.g., TGF-β), as elegantly demonstrated by Town and colleagues.

We recently reported that Toll-like receptor 2 gene deletion is also associated with Aβ42 accumulation and cognitive impairment, while TLR2 gene expression in bone marrow-derived cells rescued such a memory deficit (Richard et al., 2008). Of great interest here is that APPtg/TLR2 knockout mice had a spontaneous increase in TGF-β gene expression in immune cells adjacent to the senile plaques. We can therefore propose that macrophages are not properly activated and do not efficiently infiltrate the CNS of APP mice. This natural innate immune mechanism against endogenously produced toxic elements may prevent chronic diseases, such as AD (see Soulet and Rivest, 2008). Improving both the infiltration and immune properties of these cells will hopefully soon be an effective new therapy to cure AD. The debate about the physiological relevance of these cells in the CNS will be over once patients are cured.

View all comments by Serge Rivest

In this study, Town et al. present some fascinating findings with regard to the role of peripheral macrophages and Aβ amyloid clearance from the brains of Tg2576 mice. The authors genetically interrupted TGF-β signaling specifically in peripheral macrophages of Tg2576 mice and then evaluated Aβ pathology during aging of these mice. To the authors’ surprise, Aβ deposits were significantly attenuated in both brain parenchymal and cerebral blood vessels in these mice. Based on their data (both in vivo and in vitro), the authors suggest that the mechanism for this reduction in Aβ deposition may be due to increased infiltration of these altered peripheral macrophages into the brain and around cerebral blood vessels, resulting in increased Aβ phagocytosis. Although there are much recent data for the role of resident microglial cells in enhancing microglial-mediated phagocytosis of Aβ plaques, this is the first report to directly indicate peripheral macrophages in Aβ phagocytosis and clearance mechanisms.

Undoubtedly, these interesting results will facilitate future investigations...  Read more

In this study, Town et al. present some fascinating findings with regard to the role of peripheral macrophages and Aβ amyloid clearance from the brains of Tg2576 mice. The authors genetically interrupted TGF-β signaling specifically in peripheral macrophages of Tg2576 mice and then evaluated Aβ pathology during aging of these mice. To the authors’ surprise, Aβ deposits were significantly attenuated in both brain parenchymal and cerebral blood vessels in these mice. Based on their data (both in vivo and in vitro), the authors suggest that the mechanism for this reduction in Aβ deposition may be due to increased infiltration of these altered peripheral macrophages into the brain and around cerebral blood vessels, resulting in increased Aβ phagocytosis. Although there are much recent data for the role of resident microglial cells in enhancing microglial-mediated phagocytosis of Aβ plaques, this is the first report to directly indicate peripheral macrophages in Aβ phagocytosis and clearance mechanisms.

Undoubtedly, these interesting results will facilitate future investigations in this area; however, several questions from this report need further clarifications. Certainly, the gold standard for such experiments will be studies in chimeric mice to evaluate the effects of such altered peripheral macrophages on Aβ pathology. However, caution is warranted with regard to consequences of long-term peripheral inhibition of TGF-β signaling on macrophages. What is the effect on peripheral T cells in this scenario? Do peripheral T cells infiltrate into the CNS, and what is the phenotype of these cells? Although the authors evaluated extensively Aβ pathology in these studies, they missed an opportunity to evaluate any effects on neurodegeneration. One of the concerns of having long-term peripheral infiltration of macrophages, regardless of their phenotype, is unwanted reactions on other cell types/tissues in the brain.

In any event, these new findings do provide a unique peripheral approach for attenuating Aβ deposition in the brain and certainly warrant further investigations.

View all comments by Pritam Das