Felsky D, Roostaei T, Nho K, Risacher SL, Bradshaw EM, Petyuk V, Schneider JA, Saykin A, Bennett DA, De Jager PL. Neuropathological correlates and genetic architecture of microglial activation in elderly human brain. Nat Commun. 2019 Jan 24;10(1):409. PubMed.

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  1. This manuscript by Daniel Felsky, Philip De Jager, and colleagues provides a new perspective on the interplay between microglial activation, amyloid-β/tau pathology, and genetic risk. The authors infer that genetic risk can lead to microglial activation, which in turn results in AD. Data from our group (Sierksma et al., 2019) and Salih et al. (2018) similarly suggest that genetic risk for AD affects microglial response to amyloid-β, and that microglia activation is upstream of tau pathology, but our experimental approach is different, using a combination of gene expression analysis in response to tau or Aβ pathology and combining that with GWAS risk analysis. Both studies show a large part of risk for AD to be associated with microglia expressed genes.

    Felsky and colleagues demonstrate that a higher proportion of morphologically identified activated microglia (PAM) is associated with the presence of AD-specific pathology in two cortical regions (midfrontal and the inferior temporal cortex) as well as with cognitive decline, although the latter effect was predicted to be mediated through tau pathology. Several genomic variants were predicted to confer risk for region-specific microglial activation, and variant rs2997325T, possibly affecting expression of LINC01361, was also significantly associated with increased binding in the entorhinal cortex of a TSPO (microglia) PET ligand. Moreover, by building a polygenic risk model using the predicted GWAS variants for activated microglia in the two cortical regions, the authors could demonstrate that these variants also have predictive value for AD, although the inverse was not observed, i.e., a polygenic risk score model built from AD GWAS SNPs did not predict morphologically activated microglia. 

    Some questions remain:

    1. What causes the morphological activation of microglia? It would have been interesting to see if measures for amyloid-β or tau pathology were also predictive for the degree of microglial activation; i.e., to what extent are these three pathological observations co-occurring or can one pathological feature (e.g., amyloid-β pathology) drive the expression of the other (PAM). Transcriptomic data from AD mouse models suggest that amyloid-β pathology, and not tau pathology, triggers the microglial response, placing amyloid-β pathology as the instigator of the pathological cascade (Sierksma et al., 2019; Salih et al., 2018). These findings fit the predictions of the current paper where tangle pathology is positioned downstream of morphologically activated microglia. How activated microglia (and/or its interaction with amyloid-β accumulation) may lead to tangle formation remains to be determined.
    2. To what extent can the decline in cognitive performance be accounted for by cell loss? It has been previously demonstrated that gray matter volumes may partially mediate the effect of tau pathology on cognitive decline (Bejanin et al., 2017). A longitudinal study where structural imaging would be combined with tau- and microglia-specific PET imaging and cognitive assessment may validate their prediction that activated microglia mediate cognitive decline through tau accumulation.

    References:

    Sierksma A, Lu A, Mancuso R, Fattorelli N, Thrupp N, Salta E, Zoco J, Blum D, Buée L, De Strooper B, Fiers M. Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology. EMBO Mol Med. 2020 Mar 6;12(3):e10606. Epub 2020 Jan 17 PubMed.

    Salih DA, Bayram S, Guelfi S, Reynolds RH, Shoai M, Ryten M, Brenton JW, Zhang D, Matarin M, Botia JA, Shah R, Brookes KJ, Guetta-Baranes T, Morgan K, Bellou E, Cummings DM, Escott-Price V, Hardy J. Genetic variability in response to amyloid beta deposition influences Alzheimer's disease risk. Brain Commun. 2019;1(1):fcz022. Epub 2019 Oct 10 PubMed.

    Bejanin A, Schonhaut DR, La Joie R, Kramer JH, Baker SL, Sosa N, Ayakta N, Cantwell A, Janabi M, Lauriola M, O'Neil JP, Gorno-Tempini ML, Miller ZA, Rosen HJ, Miller BL, Jagust WJ, Rabinovici GD. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer's disease. Brain. 2017 Dec 1;140(12):3286-3300. PubMed.

    View all comments by Bart De Strooper

  2. Dr. De Jager’s group has elegantly revivified a 20-year-old technique in neuroimmunology of Alzheimer’s disease (AD)—histological assessment of microglial morphology. These investigators combined microglial stereology with high throughput genomics, transcriptomics, proteomics, imaging, and pathological analyses. From this tour de force of techniques, the authors were able to draw three primary conclusions: 1) in cortical regions, morphological evidence of microglial activation (but not proliferation) correlates with AD pathology as operationalized by Aβ deposits and paired helical filament tau; 2) microglial activation and Aβ load synergistically lead to tau pathology that induces cognitive decline; 3) a genomic propensity for activation of microglia causes increased AD risk.

    In past decades, we have linked innate immunity to AD progression and have identified mononuclear phagocytes as a primary therapeutic target. We accomplished this by 1) uncovering a circumstantial relationship between immunological traits and human AD and 2) establishing causality via genetic and pharmacological manipulation in rodent models. This paper nicely adds to the field because it shows a direct causal relationship between microglial activation and AD pathology in humans. Even more striking is the exclusivity to AD. Dr. De Jager’s group didn’t find a relationship between microglial activation and other common neuropathologies associated with aging and neuroinflammation. It is important to emphasize, though, that these results do not differentiate between different microglial activation states. This is significant, because we and others have suggested that AD progression is driven by an imbalanced innate immune system rather than generalized activation of innate immunity (Guillot-Sestier et al., 2013; Guillot-Sestier et al., 2015; Guillot-Sestier et al., 2015). 

    References:

    Guillot-Sestier MV, Town T. Innate Immunity in Alzheimer's Disease: A Complex Affair. CNS Neurol Disord Drug Targets. 2013 Apr 4; PubMed.

    Guillot-Sestier MV, Doty KR, Gate D, Rodriguez J Jr, Leung BP, Rezai-Zadeh K, Town T. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron. 2015 Feb 4;85(3):534-48. Epub 2015 Jan 22 PubMed.

    Guillot-Sestier MV, Doty KR, Town T. Innate Immunity Fights Alzheimer's Disease. Trends Neurosci. 2015 Nov;38(11):674-81. PubMed.

    View all comments by Terrence Town

  3. This article presents important data for the discussion on the role of microglia in AD pathogenesis. Yet, it is still to be determined if microglia activation is the cause of neurodegeneration or a secondary reactive process; or if neurodegeneration is secondary to microglia senescence and associated loss of microglial protection. Despite the huge amount of research based on animal models, these still only mirror limited aspects of AD pathology in humans. Furthermore, brain aging is a dynamic process and due to the prolonged lifespan of CNS microglia (in humans compared to rodents), they are more susceptible to accumulate aging-related changes (beyond specific pathological conditions).

    This study represents one of the largest studies analyzing microglia activation in human brain in the context of Alzheimer´s disease and aging. The authors elegantly approach the question starting with detailed morphological studies of microglia in neuropathologically characterized postmortem brain tissue from two large clinical cohort studies of cognitive aging, then followed by genome-wide analyses to identify the genomic architecture of microglia activation.

    This an important study supporting direct microglia involvement in AD pathogenesis, showing that both microglia activation and amyloid-β contribute to tau pathology, and that microglia activation leads to cognitive decline indirectly via the accumulation of PHF-tau.  

    Despite the large cohort and accurate diagnostic quantitation of specific pathologies (namely other proteinopathies), and certainly highlighting the close relation of activated microglia to AD pathology (Aβ and Tau), the study could be missing other neurodegenerative dementias (particularly of young onset such FTLD) where these other proteinopathies have higher burden. For instance, morphological studies have reported higher levels of activated microglia in FTLD with some differences to AD in relation to anatomical distribution (Lant et al., 2014; Taipa et al., 2017). It would be important that future studies, with similar approach, address the same question for other specified neurodegenerative dementias.

    The findings are also worth considering in the context of in vivo imaging using microglial markers. Hamelin and colleagues showed that higher initial 18F-DPA-714 binding is associated with better clinical prognosis after a two-year follow-up in AD (Hamelin et al., 2018). Interestingly, they also showed that patients with lowest initial 18F-DPA-714 binding had the greatest subsequent increase of microglial activation and unfavorable clinical outcome, while patients with highest initial 18F-DPA-714 binding had the lowest subsequent increase of microglial activation and more favorable clinical outcome, independently of the initial cortical amyloid load. With the advent of tau-targeted positron emission tomography tracers, it will be possible to extend the studies of the relationship between Aβ, tau, and activated microglia in AD and aging.

    References:

    Hamelin L, Lagarde J, Dorothée G, Potier MC, Corlier F, Kuhnast B, Caillé F, Dubois B, Fillon L, Chupin M, Bottlaender M, Sarazin M. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease. Brain. 2018 Jun 1;141(6):1855-1870. PubMed.

    Lant SB, Robinson AC, Thompson JC, Rollinson S, Pickering-Brown S, Snowden JS, Davidson YS, Gerhard A, Mann DM. Patterns of microglial cell activation in frontotemporal lobar degeneration. Neuropathol Appl Neurobiol. 2014 Oct;40(6):686-96. PubMed.

    Taipa R, Brochado P, Robinson A, Reis I, Costa P, Mann DM, Melo Pires M, Sousa N. Patterns of Microglial Cell Activation in Alzheimer Disease and Frontotemporal Lobar Degeneration. Neurodegener Dis. 2017;17(4-5):145-154. Epub 2017 Apr 27 PubMed.

    View all comments by Ricardo Taipa
    • User Profile Image Steve Barger
      University of Arkansas for Medical Sciences
    • Posted:

    This is a tour de force, integrating many sophisticated forms of analysis. In the context of many other indices of neuroinflammation and microglial malactivation, the evidence that these cells participate in AD progression is difficult to refute.

    Regarding the ordering of events, however, I must confess one concern: The analyses seem to have bypassed the regions of the brain where tau pathology begins, namely entorhinal cortex and hippocampal formation. By limiting the regional distribution to neocortex (along with striatal comparisons), the authors may have fallen victim to the temptation to "look under the lamppost." Plaques become prevalent in the neocortex before they do in the hippocampus; tau spreads to the former region only in Braak Stages IV (barely) and V. So even if microglia were capable of reacting to both amyloid and tau pathology, it begs the question to state that they precede tau pathology in regions where it is late to arrive.

    I suppose what we need is a Braak-like staging of the pattern of PAM progression.

    View all comments by Steve Barger

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