Microgliosis goes hand-in-hand with Alzheimer’s disease, but the exact staging remains murky. A neuropathological study in the January 24 Nature Communications now places one type of microglial activation into the AD pathological cascade. Researchers led by Philip De Jager at Columbia University in New York found that the more plaques and tangles in a person’s cortex, the higher the proportion of amoeboid microglia there. A statistics method that teases out causal relationships indicated that these activated cells directly promoted tau accumulation, which, in turn, triggered cognitive decline. In addition, most of the genetic variants the authors linked to activated microglia in a genome-wide association analysis boosted the risk of AD, strengthening the causal connection. “These findings suggest we should time anti-inflammatory drugs to when there is amyloid pathology, but relatively few tangles,” De Jager said.
- In human postmortem cortex, activated microglia correlate with AD pathology.
- This microglial activation appears to come after plaques but before tangles.
- Genes that heighten this activation also raise AD risk.
Other researchers praised the methodology and robustness of the finding. “This study is the largest to date directly demonstrating that microglia activation, and not abundance, is associated with AD,” Richard Bazinet at the University of Toronto wrote to Alzforum. Terrence Town at the University of Southern California, Los Angeles, was impressed by the number of different techniques used, including histological analysis, imaging, and high-throughput genomics and transcriptomics. “This paper nicely adds to the field because it shows a direct causal relationship between microglial activation and AD pathology,” he wrote.
Form Reveals Function. Microglia in healthy brain are highly ramified (left), while reactive microglia in inflamed brain are dense and globular (right). [Courtesy of Felsky et al., Nature Communications.]
Activated Microglia Linked Specifically to AD Pathology
Previous research flagged microglial changes as a key feature of Alzheimer’s disease (Davies et al., 2016). More recently, Ricardo Taipa and colleagues at the Centro Hospitalar do Porto, Portugal, found greater numbers of activated microglia in postmortem AD temporal cortices than in age-matched controls (Taipa et al., 2018). A recent review of 113 postmortem studies by Bazinet and colleagues concluded that activation of these cells, rather than their overall abundance, correlates best with AD (Hopperton et al., 2018). However, most of the individual studies in that review were small and did not include detailed pathological data or genotyping, nor correlate with cognitive assessments.
De Jager and colleagues undertook a more comprehensive analysis by leveraging data from the Religious Orders Study and the Memory and Aging Project. Both are longitudinal aging cohorts that enroll people without dementia, evaluate their cognitive and clinical health annually, and include brain donation after death. The authors selected a subset of 225 brains for analysis; 90 of these met pathological criteria for Alzheimer’s disease.
First author Daniel Felsky examined the appearance of microglia in two cortical and two subcortical regions of each. Healthy brains tend to contain slender, ramified microglia, while inflammation is associated with condensed, globular cells (see image above). The scientists found a greater proportion of such globular cells in the midfrontal and inferior temporal cortices of people with AD than in controls. In control brain, activated microglia were very rare, fewer than one in 200, whereas in Alzheimer’s cortex, the researchers counted about three times as many. This greater proportion of active microglia (PAM) in AD brain was highly significant. Moreover, people with PAM values in the highest quartile had about five times the risk of AD as those in the lowest quartile; this was comparable to the risk conferred by an ApoE4 allele in this cohort.
In contrast to these cortical regions, the PAM in two subcortical brain regions, the ventral medial caudate and the posterior putamen, were the same as in controls. “This regional specificity is an exciting finding,” Bazinet noted.
How does PAM relate to specific pathologies? The authors found the strongest correlation with amyloid plaques, the second-strongest with paired helical filaments (PHF) of tau and neurofibrillary tangles. However, high PAM did not correlate with Lewy bodies, TDP-43 deposits, or vascular pathology. The authors turned to mediation statistics, a type of regression analysis considered the gold standard for parsing the causal relationships between variables. With this, the authors identified a direct link between high PAM and PHF tau, and an indirect effect of PAM on global cognitive decline. They also found a causal link between amyloid plaques and high PAM, as well as the expected direct link between plaques and tau. Together, the data suggest that amyloid plaques and activated microglia act synergistically to promote tau pathology, which then triggers cognitive decline, the authors concluded.
This conclusion fits with data from Christian Haass at the German Center for Neurodegenerative Diseases (DZNE) in Munich. Haass found that high levels of the microglial marker sTREM2 in cerebrospinal fluid correlated with high p-tau, total tau, and cognitive decline, again suggesting that microglial activation lies upstream of tau (Dec 2016 news). Still, De Jager acknowledged that his findings do not prove causality. To get a better idea of the sequence of events, he is comparing microglial PET imaging to amyloid and tau PET in longitudinal studies.
Researchers were intrigued that activated microglia did not associate with other neuropathologies, despite inflammation being a common feature of neurodegenerative disease. De Jager suggested that neuroinflammation may occur in different brain regions in other diseases, or involve an alternate activation state of microglia. Taipa said evidence for the former exists, because he and others have found activated microglia in distinct brain regions in frontotemporal lobar degeneration (Lant et al., 2013; Taipa et al., 2017).
De Jager is investigating the possibility of different activation states. He recently analyzed the diversity of human microglia by single-cell transcriptomics, identifying 14 different subtypes (Jul 2018 news; Olah et al., 2018). Others have reported similar findings (Dec 2018 news). De Jager is profiling transcription in the activated, globular microglia to see whether they represent a single subtype, or multiple ones. The findings will provide a more precise determination of what form of microglial activation correlates with AD, he told Alzforum.
Others agreed this is an important question. Haass wondered if these globular microglia express markers of the previously identified disease-associated microglia (DAM; Jun 2017 news). For his part, Town has found that amyloid pathology prods microglia into a more inflammatory and less phagocytic state, suggesting the particular type of microglial activation is key (Feb 2015 news). “AD evolution may be driven by an imbalanced innate immune system, rather than generalized activation of innate immunity,” Town suggested.
What’s the Underlying Genetics?
For clues to what regulates microglia, De Jager and colleagues performed a GWAS using data from 2,067 participants in the ROS/MAP studies. This turned up two SNPs associated with PAM. One was rare, but the other, on chromosome 1, occurred in a third of the population. This SNP, rs2997325, associated with microglial activation in the midfrontal cortex specifically. It is unclear what the variant does. It lies near a non-coding RNA, LINC01361, but no genes. “Further study of this variant could be important in determining the mechanism of action of microglial activation in AD,” Bazinet suggested.
The authors tested the SNP’s association with microglial activation in 27 participants in the Indiana Memory and Aging Study. In that cohort, rs2997325 carriers had a higher microglial PET signal, as seen with the TSPO-binding ligand PBR28, in the left entorhinal cortex than noncarriers did, with an SUVR of around 1.6 versus 1.2. Given this, De Jager believes that much of the individual variation seen in microglial TSPO PET imaging may be a result of this SNP. Researchers may need to account for this when analyzing microglia PET to reduce noise in the data, he suggested. De Jager and colleagues adjusted for a TSPO variant that alters ligand binding.
In addition to the two genome-wide hits, the authors identified dozens of genes with weaker significance. They combined these into a polygenic risk score of microglial activation. Lo and behold, most of these genes are also AD risk genes. This suggests that having microglia that are easily activated puts people at risk of developing AD, the authors noted.
Researchers led by Bart De Strooper, Dementia Research Institute, U.K., and Mark Fiers at KU Leuven in Belgium have similar data. In a preprint on bioRχiv, they identified 11 new AD risk genes that are expressed in microglia and switched on by amyloid pathology in a mouse model. In keeping with De Jager’s model, these microglial genes are unaffected by tau pathology, suggesting they lie upstream of tau. De Strooper and others believe many genes affect AD risk by modulating the microglial response to Aβ. Numerous known AD genes, such as TREM2, CD33, and ABCA7, are primarily expressed in microglia. A recent large GWAS supports the idea that a large portion of AD risk comes from microglial gene expression (Jun 2017 news).—Madolyn Bowman Rogers
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- Invading Microglia Unleash Neurodegeneration in 3D AD Culture
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