‘Innate immune memory’ is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished, training and tolerance, which are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages, microglia, that persists for at least six months. Strikingly, in a mouse model of Alzheimer’s pathology, immune training exacerbates cerebral β-amyloidosis while tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's β-amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases.

Key Points• In vitro analysis of VKORC1 mutations perfectly reflects patients' warfarin resistance phenotypes.• In silico docking of warfarin on a VKORC1 model reveals a putative docking site in agreement with the locations of OACR-associated mutations.Since the discovery of warfarin-sensitive vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), 26 human VKORC1 (hVKORC1) missense mutations have been associated with oral anticoagulant resistance (OACR). Assessment of warfarin resistance using the "classical" dithiothreitol-driven vitamin K 2,3-epoxide reductase (VKOR) assay has not reflected clinical resistance phenotypes for most mutations. Here, we present half maximal inhibitory concentrations (IC 50 ) results for 21 further hVKORC1 mutations obtained using a recently validated cell-based assay (J Thromb Haemost 11(5):872). In contrast to results from the dithiothreitol-driven VKOR assay, all mutations exhibited basal VKOR activity and warfarin IC 50 values that correspond well to patient OACR phenotypes. Thus, the present assay is useful for functional investigations of VKORC1 and oral anticoagulant inhibition of the vitamin K cycle. Additionally, we modeled hVKORC1 on the previously solved structure of a homologous bacterial enzyme and performed in silico docking of warfarin on this model. We identified one binding site delineated by 3 putative binding interfaces. These interfaces comprise linear sequences of the endoplasmic reticulum-lumenal loop (Ser52-Phe55) and the first (Leu22-Lys30) and fourth (Phe131-Thr137) transmembrane helices. All known OACR-associated hVKORC1 mutations are located in or around these putative interfaces, supporting our model. (Blood. 2013;122(15):2743-2750

This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD).Theories have been postulated, tested, and modified over several decades. The findings have further bolstered the belief that microglia-mediated inflammation is both a product and contributor to AD pathology and progression. Distinct microglia phenotypes and their function, microglial recognition and response to protein aggregates in AD, and the overall role of microglia in AD are areas that have received considerable research attention and yielded significant results. The following article provides a historical perspective of microglia, a detailed discussion of multiple microglia phenotypes including dark microglia, and a review of a number of areas where microglia intersect with AD and other pathological neurological processes. The overall breadth of important discoveries achieved in these areas significantly strengthens the hypothesis that neuroinflammation plays a key role in AD. Future determination of the exact mechanisms by which microglia respond to, and attempt to mitigate, protein aggregation in AD may lead to new therapeutic strategies.

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Background Microglial cells play an important role in the pathogenesis of Alzheimer’s disease. We have previously shown that microglia activate the Hypoxia inducible factor‐1α (HIF‐1α) signalling pathway in response to cerebral β‐amyloidosis in a mouse model of Alzheimer’s pathology (Wendeln et al., Nature, 2018). Importantly, we also found that activation of microglial HIF‐1α signalling correlated with disease severity and that HIF‐1α levels were particularly elevated in plaque‐associated microglia. Method In the experiments presented here, we analyzed the role of microglial HIF‐1α in promoting cerebral β‐amyloidosis by characterizing pathological hallmarks and microglial activation states in two APP transgenic mouse models with an induced HIF‐1α knockout (KO) in microglia cells. Result Our results indicate that the lack of HIF‐1α in microglia increases their clustering around amyloid‐β plaques and alters the microglial phenotype and brain inflammatory state. While plaque load was indistinguishable in mice with/out microglial HIF‐1α, our data indicate that the increase in plaque‐associated microglia limits plaque‐induced neuronal damage. Conclusion Our data indicate that HIF‐1α inhibition alters the microglial phenotype, leading to an increased number of microglia around amyloid‐β plaques, thereby protecting neurons.

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