. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nat Neurosci. 2017 Aug;20(8):1052-1061. Epub 2017 Jun 19 PubMed.

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  1. I think this is an extremely important and insightful piece of work, which firmly puts the microglial response as key to Alzheimer pathogenesis. It builds on the work of Jones et al. (2010), as well as our own work and on both human genetics and transgenic animals (Matarin et al., 2015; Gagliano et al., 2016). 

    These together clearly show that genetic variability in how the brain responds to Aβ deposition is key to determining who gets the disease. This work perhaps serves as the genetic underpinning of the "cellular phase" of Alzheimer’s disease (De Strooper and Karran, 2016). 

    This paper has been available for several months on BioRxiv. I think this also is an important event.  Too much science is being held up by the slow reviewing process. It is great that the authors chose to make this seminal work available before acceptance. I hope this, too, turns out to be a marker for the future.

    References:

    . Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One. 2010;5(11):e13950. PubMed.

    . A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 2015 Feb 3;10(4):633-44. Epub 2015 Jan 22 PubMed.

    . Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases. Ann Clin Transl Neurol. 2016 Dec;3(12):924-933. Epub 2016 Nov 4 PubMed.

    . The Cellular Phase of Alzheimer's Disease. Cell. 2016 Feb 11;164(4):603-15. PubMed.

    View all comments by John Hardy
  2. Huang, Goate, and colleagues made remarkable findings that underscore the importance of noncoding genetic variation in regulation of gene expression relevant to disease. In particular, it highlights a function for the myeloid transcription factor PU.1 and the microglial response as a vital component of AD pathogenesis.

    The results are consistent with our published work showing that AD-associated genetic risk variants are enriched in the noncoding regions that regulate immune response genes, suggesting that predisposition to AD is encoded in the immune system, and furthermore identifying PU.1 as a master regulator of the AD immune response (Gjoneska et al., 2015). 

    The implications of this work are very significant, as it provides novel avenues for therapeutic interventions suggesting that regulation of PU.1 expression or its relevant target genes can be used as an effective strategy for AD treatment. It is an exciting possibility that warrants further exploration.

    References:

    . Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature. 2015 Feb 19;518(7539):365-9. PubMed.

    View all comments by Elizabeth Gjoneska
  3. This multicenter study led by Alison Goate conducted a large-scale, genome-wide survival analysis on thousands of AD cases and control samples to uncover loci associated with age of onset of AD. The authors discovered a CSF Aβ42-associated SNP in the previously reported CELF1 AD risk locus. They found that this locus was significantly associated through a protective allele with reduced SPI1 (PU.1), a lineage-determining transcription factor for myeloid cells.

    Recent analysis of microglia enhancers has revealed the molecular mechanisms, which regulate microglia gene expression programs (Gosselin et al., 2014; Matcovitch-Natan et al., 2016). Active enhancers in microglia contain DNA sequences bound to the macrophage lineage-determining factor PU.1 (Heinz et al., 2010). 

    PU.1 cooperates with microglia-specific enhancer regions of the Mef2 family, which is exclusively expressed in microglia as compared to other peripheral immune cells (Butovsky et al., 2014; Matcovitch-Natan et al., 2016). This factor has been proposed as the responsible partner of PU.1 in establishing a microglia-specific molecular signature (Lavin et al., 2014). In addition, motif analysis of PU.1 binding has revealed enrichment for consensus sequences for Smad3, Mef2, and Mafb (Gosselin et al., 2014). These studies suggest that these transcription factors cooperate with PU.1 in the establishment of microglia-specific enhancer profiles. Secondary transcription factors included SMAD proteins, which are induced by TGFβ and contribute to microglia transcription of specific target genes (Butovsky et al., 2014; Gosselin et al., 2014).

    The discovery in this study is unsurprising because recently, genetic and molecular evidence obtained from brain homogenates has implicated myeloid cells in the etiology of AD. This includes Bin1, Trem2 and CD33 molecules related to phagocytic and immunomodulatory functions of myeloid cells.

    However, myeloid cells such as microglia represent a minor fraction of the tissue in these analyses. Thus, the investigators analyzed cis-eQTL effects of the AAOS-associated SNPs in human monocytes and macrophages. They discovered the key transcriptional regulator of the myeloid cells. It provides the core transcriptional regulation of microglia and blood monocytes, and may regulate the expression of multiple AD-associated genes in myeloid cells. Thus, this study provides important evidence of the implication of innate immunity in the etiology and disease progression of AD.

    References:

    . Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014 Dec 4;159(6):1327-40. PubMed.

    . Microglia development follows a stepwise program to regulate brain homeostasis. Science. 2016 Aug 19;353(6301):aad8670. Epub 2016 Jun 23 PubMed.

    . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010 May 28;38(4):576-89. PubMed.

    . Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2014 Jan;17(1):131-43. Epub 2013 Dec 8 PubMed.

    . Nitric oxide prevents aortic neointimal hyperplasia by controlling macrophage polarization. Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1739-46. Epub 2014 Jun 12 PubMed.

    View all comments by Oleg Butovsky
  4. This is a very interesting finding, providing an association of PU.1 with age of onset of Alzheimer's disease. The authors provide solid evidence of the roles of the detected genetic variability on monocyte function, but I guess we are all asking ourselves: Is this informing about altered microglial function in AD? This is an exciting prospect that we can frame on existing literature.

    In this sense, we previously reported an increased expression of PU.1 in microglia in both AD brain (Gómez-Nicola et al., 2013Olmos-Alonso et al., 2016) and in a model of AD-like pathology (Olmos-Alonso et al., 2016). Although PU.1 is expressed by microglia in the healthy brain, its levels are unregulated during AD, with functions not fully understood. However, we do know that PU.1 regulates the expression of the components of the CSF1R pathway, helping to drive a prominent microglial proliferative response that can be observed in AD, both in humans and mice (Olmos-Alonso et al., 2016). It is therefore tempting to link the observed roles of PU.1 with those of CSF1R, and therefore suggest that the observed beneficial effects of targeting CSF1R (Olmos-Alonso et al., 2016; Dagher et al., 2015; Spangenberg et al., 2016) are correlative with the now-reported beneficial effects of mutation of PU.1.

    It will be exciting to see follow-up studies on the specific roles of these mutations on microglial PU.1, as this will get us closer to a full understanding of the role of these cells in AD.

    References:

    . Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain. 2016 Mar;139(Pt 3):891-907. Epub 2016 Jan 8 PubMed.

    . Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci. 2013 Feb 6;33(6):2481-93. PubMed.

    . Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation. 2015 Aug 1;12:139. PubMed.

    . Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain. 2016 Apr;139(Pt 4):1265-81. Epub 2016 Feb 26 PubMed.

    View all comments by Diego Gómez-Nicola

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