. Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat Neurosci. 2009 Nov;12(11):1361-3. PubMed.

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  1. The demonstration by Grathwohl et al. that substantial depletion of microglia has no consequences for Aβ deposition is indeed intriguing. However, this finding must be taken in context of a good deal of data indicating that microglia do participate in the sequelae of events occurring in AD and in APP transgenic models, much of which come from studies enlisting elegant gene- or cell-ablation approaches such as those applied here. For instance, genetic ablation of Toll-like receptor 2 (Richard et al., 2008) or CCR2 (El Khoury et al., 2007) exacerbates plaque deposition.

    More importantly, many hypotheses about the roles of microglia in AD involve events downstream of amyloidogenesis, such as synaptic dysregulation or frank neurotoxicity. The sole parameter assessed in this paper that has any possible link to such downstream events was APP staining in dystrophic neurites. But no compelling claims had ever been made for a connection between microglial actions and these structures; the APP staining is likely a consequence of the transgene itself. It would be more relevant to survey markers of synapse integrity and function, as well as tau phosphorylation. Indeed, several lines of investigation indicate that microglia play tonic roles in normal synapse formation, modulation, and removal (Bessis et al., 2007; Wake et al., 2009). If this is the case, it is difficult to imagine that their activation in AD does not impact synaptic function in some way.

    There is also compelling evidence that one consequence of FAD mutations is dependent upon microglia; namely, microglia expressing mutant forms of presenilin-1 alter the fate of neural progenitor cells (Choi et al., 2008). Relatedly, it would certainly be important to characterize the behavioral profile of mice manipulated in the manner of Grathwohl et al.

    References:

    . Microglial control of neuronal death and synaptic properties. Glia. 2007 Feb;55(3):233-8. PubMed.

    . Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron. 2008 Aug 28;59(4):568-80. PubMed.

    . Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. PubMed.

    . Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J Neurosci. 2008 May 28;28(22):5784-93. PubMed.

    . Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009 Apr 1;29(13):3974-80. PubMed.

    View all comments by Steve Barger