After Immunotherapy, Amyloid Clearance Comes Down to Microglial Moods
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Plaques all but vanish in response to some Aβ immunotherapies. Scientists suspect microglia orchestrate the mop-up, but don’t know how, exactly. Now, David Gate of Northwestern University in Chicago and colleagues offer a snapshot of the cellular response in the human brain. As reported March 6 in Nature Medicine, they used spatial transcriptomics to study postmortem tissue from 13 people who had been immunized previously with AN1792—an Aβ vaccine—and from one woman who had received lecanemab, a therapeutic antibody, as well as untreated controls in those trials.
- Spatial transcriptomics on human brains parsed microglial reactions to amyloid immunotherapy.
- Both a vaccine and a therapeutic antibody summoned these cells to plaques.
- Responders expressed TREM2, ApoE, complement, and immune genes.
In all samples, microglia were spotted encircling remnants of Aβ plaques, while expressing abundant TREM2, ApoE, SPP1, and complement, to name a few proteins. In non-immunized people with AD, or in people who mounted a sluggish response to AN1792, microglia encircled plaques but had not cleared them. These stymied cells expressed some responsive genes such as TREM2 and ApoE, but not others, including complement. Broadly speaking, the findings distinguish helpful and maladaptive responses to immunotherapy, and give scientists hints about which pathways to promote with therapies.
“This paper is a key contribution with far-reaching implications for the understanding of anti-amyloid antibody-based immunotherapies and the crucial role of microglial activity in efficient amyloid clearance,” wrote Lis de Weerd and Christian Haass of the German Center for Neurodegenerative Diseases in Munich.
Cynthia Lemere of Brigham and Women’s Hospital in Boston commended the authors for pulling together such a complex set of data. To her mind, it came as no surprise that complement signaling emerged as a key pathway in amyloid clearance in response to both immunization schemes. The findings are consistent with mouse research from her lab, which shows complement to be a double-edged sword promoting both plaque clearance and potentially harmful inflammation (Jun 2017 news; Aug 2023 conference news).
Antibodies are the business end of both types of immunotherapy. AN1792 was the first vaccine to rile the human immune system against Aβ plaques. In a Phase 2a trial that began in 2000, it did just that, provoking a robust antibody response in some trial participants, all of whom had dementia. However, havoc ensued when T cells joined the fray, igniting meningoencephalitis in 6 percent of the participants and halting the program. Years later, when former participants died, neuropathological analysis showed that the more antibodies a person had mounted in response to the vaccine, the more plaques were cleared from his or her brain (Nicoll et al., 2006; Holmes et al., 2008; Nicoll et al., 2019). That such antibodies did indeed rid the brain of plaques, and may have even slowed cognitive decline, spurred the subsequent development of passive immunotherapies (May 2003 news).
Now, with high-resolution omics at their fingertips, first author Lynn van Olst and colleagues took a closer look at those same samples to dissect what cellular and molecular mechanisms had been in play during these pioneering AD vaccine trial participants. Meanwhile, three participants in the open-label extension of the Clarity Phase 3 trial of the lecanemab antibody died of intracerebral hemorrhages brought on by a fatal combination of edema (a side effect of the immunotherapy), cerebral amyloid angiopathy, and treatment with blood thinners (Jan 2023 news; Jan 2024 news). One, a 65-year-old woman, died at Northwestern University Hospital. Gate and colleagues included samples from her brain.
For the AN-1792 study, the scientists analyzed frontal cortex samples from 25 cases: 13 people with AD who were immunized with AN1792, six people with AD who were not immunized, and six controls who had died without neurological disease. Using the Visium spatial transcriptomics platform from 10xGenomics, they measured levels of some 25,000 transcripts in each of 4,992 spots across a 6.5 mm x 6.5 mm area of 5-micron-thin slices. Each spot contained one to 10 cells. They discovered profound gene-expression differences across groups. Particularly within cortical layer III, immunized people (iAD) had more transcripts for TREM2 and ApoE, both considered integral to the microglial response to Aβ. They also had expressed alpha-2-macroglobulin (A2M) and caveolae-associated protein 1 (CAVIN1), which are involved in inflammation and lysosomal function, respectively. On the other hand, genes encoding heat-shock proteins were turned down in immunized relative to non-immunized people with AD (nAD).
A New Look at AN1792. Immunization with AN1792 instigated B cells to churn out anti-Aβ antibodies (left). Spatial transcriptomics of frontal cortex can show how they affected the brain. (NND, non-neurologic disease controls; nAD, non-immunized people with AD; iAD, immunized people with AD. [Courtesy of van Olst et al., Nature Medicine, 2025.]
To zero in on responses driving plaque removal, the scientists split the immunized cohort into those with limited versus those with extensive Aβ clearance as gauged by the moth-eaten appearance of lingering Aβ deposits, Gate told Alzforum. Then, superimposing Aβ staining with spatial transcriptomics maps, they compared microglial signatures near plaques between groups.
Some highlights? Relative to microglia in the non-immunized group, plaque-adjacent ones in immunized people were flush with transcripts encoding ApoE, TREM2, A2M, RAB13, FAM107A, and other known amyloid response genes, including LAMP1, ITGAX, and APOC1; heat-shock proteins were turned down. Confocal imaging confirmed a handful of these changes at the protein level.
Strikingly, some plaque-associated microglia had gobs of ApoE within their processes, while the plaques themselves were loaded with the apolipoprotein. This is consistent with old data placing ApoE in the midst of plaques, and with a recent report that ApoE forms aggregates alongside Aβ within microglial lysosomes, a match that might seed plaque formation (Namba et al., 1991; Jul 2018 conference news; Oct 2024 news).
Loaded. Microglial cell (red) grappling an A plaque (white) contains large deposits of ApoE (green) in its processes. [Courtesy of van Olst et al., Nature Medicine, 2025.]
Referencing published human microglial states from single-cell sequencing studies, the authors found that immunized AD brains had fewer microglia that were in a stress-responsive, inflammatory, or glycolytic state, and more cells that were in a ribosome biogenesis state (Oct 2023 news on Sun et al., 2023). In contrast, non-immunized people with AD had more stress-responsive and inflammatory microglia surrounding plaques.
Microglia also took on distinct signatures depending on the extent of amyloid clearance in their neighborhood. For example, in cases of extensive plaque clearance, the cells upregulated myristoylated alanine-rich C kinase substrate, a protein involved in cell motility and phagocytosis, and fibroblast growth factor receptor 3 in addition to ApoE. Scientists have linked MARCKS to activation of microglia by Aβ (Hasegawa et al., 2001). FGFR3 is a receptor for FGF2, which is churned out by neurons in response to Aβ oligomers, summoning microglia to the scene. Van Olst and colleagues also turned up genes involved in oxidative phosphorylation and adipogenesis.
In cases where clearance was limited, phagocytosis-promoting genes, including TREM2, A2M, and LAMP1 were more strongly dialed up, while complement and unfolded protein response pathways were turned down and the ApoE response was weaker. Regardless of clearance, microglia cranked up STAT5-IL-2 signaling, as well as PYCARD, an inflammasome activator, relative to the non-immunized group.
Notably, there were signs that microglia in the group with extensive Aβ clearance (iAD-ext) may have been on their way back to homeostasis, Gate said. For example, their transcriptomes nudged closer to those of microglia in non-neurologic disease controls, suggesting they were using oxidative phosphorylation instead of glycolysis, the latter of which is cranked up to fuel microglial responses. Meanwhile, those in the midst of limited clearance (iAD-lim) were mired in inflammatory frustration, with signatures more aligned with those in non-immunized people with AD. “These findings suggest that effective Aβ clearance relies on balanced microglial metabolic states that also protect against Aβ neurotoxicity,” the authors wrote.
Lecanemab Rallies Troops
To compare this to a lecanemab response, van Olst had precious samples from the woman who died after three doses of lecanemab but also tPA, which is now contraindicated. Because her brain was preserved with extensive analysis in mind, van Olst and colleagues were able run a barrage of single-cell transcriptomics, spatial transcriptomics, and proteomics on her hippocampus and frontal, temporal, and parietal cortices, comparing with data from three untreated, age-matched people with Alzheimer’s who had died with a comparable amount of AD pathology and cerebral amyloid angiopathy. All four carried two copies of ApoE4. No control of a lecanemab-treated AD case without tPA-involved cause of death was available.
While the AN1792 participants had been immunized many years prior to death, the lecanemab patient died in the early phase of treatment, when a burgeoning immune response was in full swing, albeit during extensive hemorrhaging brought on by ARIA and tPA. To mitigate the effects of the latter, scientists focused on activity in the vicinity of plaques. This was most apparent in her temporal and parietal cortices, where microglia had dramatically revved up expression of genes involved in complement signaling, lysosomal function, protein degradation, and vascular pathways. From these regions, the scientists identified two main subtypes of microglia that were only found in the lecanemab case, not in any of the other 25 cases in this study series. One, called Mg-2, expressed a mix of DAM and homeostatic markers, along with the TAM receptor Axl, complement C3, CD74, and SPP1. The other, Mg-4, was standard DAM, revving up ITGAX, LPL, MMP9, CHI3L1, and SPP1. Notably, both clusters had ramped up TREM2, ApoE, and complement genes.
Surrounded. Confocal images show Iba1-expressing myeloid cells (red) circling deposits of Aβ (white) and ApoE (green). There was more of this in the lecanemab case (right) than in an untreated person with AD (left). [Courtesy of van Olst et al., Nature Medicine, 2025.]
The scientists deployed spatial transcriptomics to see exactly where these and other cells sat in relation to amyloid deposits. Immediately near plaques, a host of genes involved in complement signaling, lysosomal function, protein degradation, and lipid metabolism were up. Many of them matched the Mg-2 and Mg-4 subtypes the single-cell RNA sequencing had identified. Plaque-adjacent microglia churned out ApoE as well. Confocal microscopy illuminated microglia tightly encircling plaques that were loaded with the apolipoprotein (image at right).
Van Olst pinpointed one cadre of genes, dubbed cluster 3, that dramatically cranked up only in the spots with the most Aβ, and only in the lecanemab case. It included complement and IL-2-STAT5 signaling genes, as well as ApoE, TREM2, SPP1, APOC1, and Cathepsin B (image below).
Plaque-Busting Cadre? Cluster 3 genes ramped up with increasing density of Aβ in response to lecanemab treatment (red) but not in non-immunized people with AD (blue).
Finally, the scientists used high-definition spatial transcriptomics, which measures fewer transcripts but does so at single-cell resolution. They spotted many of the genes they suspected of responding to lecanemab expressed in microglia huddled around plaques. There were far more abundant in the lecanemab-treated case than in controls.
This analysis also visualized other cell types near plaques, for example astrocytes and vascular cells. The scientists are studying those now, Gate told Alzforum (image below).
Myeloid Mobilized. High-definition spatial transcriptomics (left) reveals myeloid cells (fuchsia) huddling around plaques (red). This recruitment is more robust in the lecanemab-treated case (left panel) than in a non-immunized control. Right shows the proportion of different cell type near the plaques. [Courtesy of van Ostl et al., Nature Medicine, 2025.]
Do mobilized microglia transition back to a homeostatic state after long-term treatment with lecanemab, as implied by some of the AN1972 samples? If so, can they be safely reactivated if amyloid plaques re-emerge? These are critical questions left unanswered, wrote de Weerd and Haass. Ongoing mouse studies in their lab suggest that, indeed, microglia ditch their DAM identity after they are done removing amyloid (comment below).
Lemere raised caveats about the study, including the small sample size, particularly in the lecanemab data. She particularly noted that complement ramps up rapidly in response to brain hemorrhage, which caused the woman’s death. “These acute changes were probably underway in the lecanemab patient’s brain, so it may be difficult to tease apart what was due to lecanemab-mediated plaque removal versus the fallout from the intracerebral hemorrhages,” she wrote. “In the future, it will be interesting to look at brain tissues of AD patients who had transient ARIA, recovered, and lived for at least a few years after amyloid removal to determine long-term microglial and macrophage gene changes,” she added (comment below).
Giulia Albertini and Bart De Strooper of KU Leuven in Belgium see the findings dovetailing with their work demonstrating that microglia are required to orchestrate amyloid removal in response to lecanemab in mice xenografted with human microglia. Similar approaches will help determine whether microglia are not only necessary for Aβ removal, but might also contribute to the observed side effects, such as edema, they noted. “In an era where anti-Aβ therapies are transitioning into widespread clinical practice, research into elucidating their working mechanisms, as well as their side effects, is crucial,” they wrote (comment below).—Jessica Shugart
References
News Citations
- Sans Complement: Amyloid Grows, Synapses and Memory Stay
- Is ARIA an Inflammatory Reaction to Vascular Amyloid?
- Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
- Should People on Blood Thinners Forego Leqembi?
- Brain of Woman Who Died on Leqembi Shows Worst-Case Scenario
- TREM2: Diehard Microglial Supporter, Consequences Be DAMed
- A Match Made in Microglia? ApoE and Aβ Click in Lysosomes, Seeding Plaque
- Stunning Detail: Single-Cell Studies Chart Genomic Architecture of AD
Therapeutics Citations
Paper Citations
- Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol. 2006 Nov;65(11):1040-8. PubMed.
- Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.
- Nicoll JA, Buckland GR, Harrison CH, Page A, Harris S, Love S, Neal JW, Holmes C, Boche D. Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer's disease. Brain. 2019 Jul 1;142(7):2113-2126. PubMed.
- Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991 Feb 8;541(1):163-6. PubMed.
- Sun N, Victor MB, Park YP, Xiong X, Scannail AN, Leary N, Prosper S, Viswanathan S, Luna X, Boix CA, James BT, Tanigawa Y, Galani K, Mathys H, Jiang X, Ng AP, Bennett DA, Tsai LH, Kellis M. Human microglial state dynamics in Alzheimer's disease progression. Cell. 2023 Sep 28;186(20):4386-4403.e29. PubMed.
- Hasegawa H, Nakai M, Tanimukai S, Taniguchi T, Terashima A, Kawamata T, Fukunaga K, Miyamoto E, Misaki K, Mukai H, Tanaka C. Microglial signaling by amyloid beta protein through mitogen-activated protein kinase mediating phosphorylation of MARCKS. Neuroreport. 2001 Aug 8;12(11):2567-71. PubMed.
Further Reading
No Available Further Reading
Primary Papers
- van Olst L, Simonton B, Edwards AJ, Forsyth AV, Boles J, Jamshidi P, Watson T, Shepard N, Krainc T, Argue BM, Zhang Z, Kuruvilla J, Camp L, Li M, Xu H, Norman JL, Cahan J, Vassar R, Chen J, Castellani RJ, Nicoll JA, Boche D, Gate D. Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease. Nat Med. 2025 Mar 6; Epub 2025 Mar 6 PubMed.
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Comments
German Center for Neurodegenerative Diseases (DZNE)
Biomedizinisches Centrum (BMC), Biochemie & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
This paper is a key contribution, with far-reaching implications for the understanding of anti-amyloid antibody-based immunotherapies and the crucial role of microglial activity in efficient amyloid clearance. The authors identified significant unique and common transcriptomic and proteomic changes across two different treatment paradigms: active immunization with AN1792 and passive immunization with lecanemab.
Notably, microglia spatially associated with amyloid plaques exhibited increased expression of TREM2 and ApoE compared to such cells in non-immunized controls, regardless of whether the treatment was active or passive. Moreover, the upregulation of TREM2 and ApoE correlated with anti-AN1792 antibody titer and enhanced amyloid plaque clearance. This may be in line with our previous findings showing that a longitudinal increase in CSF TREM2 of DIAN patients is associated with lower amyloid PET, slower cognitive decline, and less brain shrinkage in presymptomatic carriers (Morenas-Rodríguez et al., 2022). In addition, we previously demonstrated that anti-amyloid antibody-mediated uptake of aggregated amyloid is partially TREM2-dependent (Xiang et al., 2016). However, our study was conducted using cultured cells, whereas the current study provides patient-derived data.…More
A critical question, which is not yet answered with this study, is what happens to microglia after long-term passive immunotherapy and chronic induction of amyloid plaque removal. Do they revert to a homeostatic state, and can they be reactivated if amyloid plaques re-emerge? In our ongoing study, which will be presented at the AD/PD meeting in Vienna, we provide evidence that microglia do return to a more homeostatic state under chronic treatment conditions in an amyloid mouse model. They downregulate TREM2 and other markers of the DAM signature and also show reduced glucose uptake in correlation to plaque load. However, microglia at remaining plaques are still capable of inducing DAM activation. While this may be promising, it remains unclear how and if microglia still respond to amyloid pathology when treatment is resumed after it was paused.
Importantly, the current study supports the idea that boosting TREM2 function could have therapeutic potential. Several TREM2 agonists have already been developed, some of which stimulate amyloid plaque clearance in mouse models of amyloidogenesis (Schlepckow et al., 2023).
The current findings further suggest that combining anti-amyloid antibodies with TREM2 agonists may represent an innovative strategy to enhance amyloid clearance in patients. However, in our lab, this co-treatment approach has not yet been successful. Moreover, very recent findings from our lab also suggest that TREM2 agonism may have opposing effects in populations of high- versus mid-TREM2-expressing microglia that could potentially impact treatment efficacy (Feiten et al., 2024). Further research into TREM2 agonists is warranted before clinical use in patients.
Nevertheless, the findings described in this publication support a pivotal role of TREM2 in anti-amyloid immunotherapy and suggest that this function may be further explored therapeutically.
References:
Morenas-Rodríguez E, Li Y, Nuscher B, Franzmeier N, Xiong C, Suárez-Calvet M, Fagan AM, Schultz S, Gordon BA, Benzinger TL, Hassenstab J, McDade E, Feederle R, Karch CM, Schlepckow K, Morris JC, Kleinberger G, Nellgard B, Vöglein J, Blennow K, Zetterberg H, Ewers M, Jucker M, Levin J, Bateman RJ, Haass C, Dominantly Inherited Alzheimer Network. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study. Lancet Neurol. 2022 Apr;21(4):329-341. PubMed.
Xiang X, Werner G, Bohrmann B, Liesz A, Mazaheri F, Capell A, Feederle R, Knuesel I, Kleinberger G, Haass C. TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance. EMBO Mol Med. 2016 Sep 1;8(9):992-1004. PubMed.
Schlepckow K, Morenas-Rodríguez E, Hong S, Haass C. Stimulation of TREM2 with agonistic antibodies-an emerging therapeutic option for Alzheimer's disease. Lancet Neurol. 2023 Nov;22(11):1048-1060. PubMed.
Feiten AF, Dahm K, vanLengerich B, Suh JH, Reifschneider A, Wefers B, Bartos LM, Wind-Mark K, Schlepckow K, Ulas T, De-Domenico E, Becker M, Khalin I, Davis SS, Wurst W, Plesnila N, Neher JJ, Brendel M, Lewcock JW, DiPaolo G, Capell A, Monroe KM, Schultze JL, Haass C. TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism. 2024 Jul 22 10.1101/2024.07.18.604115 (version 1) bioRxiv.
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School
These studies allow an initial glimpse into the microglial response and Aβ removal following active Aβ vaccination and passive AŴ immunization. The following caveats should be kept in mind:
References:
Holste K, Xia F, Garton HJ, Wan S, Hua Y, Keep RF, Xi G. The role of complement in brain injury following intracerebral hemorrhage: A review. Exp Neurol. 2021 Jun;340:113654. Epub 2021 Feb 20 PubMed.
VIB/KU Leuven
UK Dementia Research Institute@UCL and VIB@KuLeuven
In an era where anti-Aβ therapies are transitioning into widespread clinical practice, research into elucidating their working mechanisms, as well as their side effects, is crucial. Lynn van Olst, David Gate, and colleagues present a beautifully executed study that not only leverages spatial transcriptomics and single-cell RNA sequencing but also integrates proteogenomics to dissect the cellular responses to anti-Aβ immunotherapy. This work, although descriptive, nicely complements our own recent work (Albertini et al., 2024) that is currently under revision, where we showed in a human xenograft model that lecanemab only removes amyloid plaques in the presence of human microglia, demonstrating the crucial role of these cells in the response to antibody therapies.…More
Van Olst and colleagues examine postmortem brains from patients treated in the early AN1792 immunotherapy trial, which took place roughly two decades ago (Holmes et al., 2008). This trial was the first to actively immunize AD patients against Aβ1–42, but it was discontinued in 2002 after some participants developed aseptic meningoencephalitis. Despite these safety concerns, long-term follow-up studies revealed substantial Aβ plaque removal in a subset of patients.
The authors compare the phenotypes of plaque niches from patients with limited versus extensive Aβ clearance and show that extensive clearance is associated with the upregulation of oxidative phosphorylation and adipogenesis transcriptional programs, while limited clearance is linked to downregulation of complement and unfolded protein response pathways. This suggests that effective Aβ clearance depends on balanced metabolic states that also help protect against Aβ neurotoxicity.
Furthermore, they examined the neuroimmune response in a single lecanemab-treated patient who developed stroke-like symptoms and passed away after TPA treatment (Castellani et al., 2023; Reish et al., 2023). In this patient, they identify upregulated genes (for example, SPP1 and APOC1) and phenotypes (characterized by APOE and TREM2 expression) associated with Aβ clearance that are remarkably similar to phenotypes we identified in our human xenograft study, which is an in vivo study entirely focused on passive immunization.
While their spatial transcriptomic data are fascinating, spatial resolution remains a critical limitation in confidently attributing specific transcriptional changes to microglia. As highlighted by our recent work (Mallach et al., 2024), the interpretation of cell-type-specific responses using ST is complicated by challenges in accurate cell segmentation, RNA diffusion, and the inability to distinguish fine-grained cellular interactions. In the absence of high-confidence single-cell resolution, some of the transcriptomic changes observed in the study by Gate et al. could be influenced by the mixed cellular environment around Aβ plaques, particularly given the well-established microglia-astrocyte crosstalk in neuroinflammation.
Another limitation of the study is that the work describes the end stage in postmortem material, which makes it difficult to make causal inferences.
We focused our study entirely on lecanemab because the mechanism by which this drug removes amyloid plaques from the brain is controversial (Sun et al., 2023; Bacskai, et al., 2002; Garcia-Alloza et al., 2007; Das et al., 2003). While it has been proposed that the antibody works in essence by binding specific toxic oligomeric assemblies, we demonstrate that lecanemab firmly binds to amyloid plaques and in that way activates microglia. In our experiments, these cells turn out to be both necessary and sufficient to mediate amyloid plaque removal, corroborating the pivotal role of these cells in the disease cascade (Baligács et al., 2024; Mancuso et al., 2024; Mancuso et al., 2019).
Ultimately, van Olst et al. provide an excellent molecular atlas of cellular states in immunized AD patients, while our study demonstrated that microglial activation is not just correlated with but required for lecanemab-driven Aβ clearance. These two complementary and independent lines of evidence together offer a comprehensive view of how these antibodies work and provide crucial insights that may help improve future anti-Aβ therapies—a true breakthrough in the field.
Similar complementary approaches will now need to focus on further dissecting these mechanisms—and determining whether microglia are not only necessary for Aβ removal but might also become inflammatory and contribute to the observed side effects, an aspect that emerged in both studies.
References:
Albertini A, Zielonka M, Cuypers ML, van Lieshout V, Snellinx A, Pasciuto E, Wolfs L, Craessaerts K, Horré K, Jaspers T, Fiers M, Dewilde M, De Strooper B. Using anti‐Aβ antibodies to modulate the multi‐pronged human microglia response to Aβ pathology. Alzheimers Dement. 2025 Jan 3 Alzheimers & Dementia
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.
Castellani RJ, Shanes ED, McCord M, Reish NJ, Flanagan ME, Mesulam MM, Jamshidi P. Neuropathology of Anti-Amyloid-β Immunotherapy: A Case Report. J Alzheimers Dis. 2023;93(2):803-813. PubMed.
Reish NJ, Jamshidi P, Stamm B, Flanagan ME, Sugg E, Tang M, Donohue KL, McCord M, Krumpelman C, Mesulam MM, Castellani R, Chou SH. Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke. N Engl J Med. 2023 Jan 4; PubMed.
Mallach A, Zielonka M, van Lieshout V, An Y, Khoo JH, Vanheusden M, Chen WT, Moechars D, Arancibia-Carcamo IL, Fiers M, De Strooper B. Microglia-astrocyte crosstalk in the amyloid plaque niche of an Alzheimer's disease mouse model, as revealed by spatial transcriptomics. Cell Rep. 2024 Jun 25;43(6):114216. Epub 2024 May 30 PubMed.
Sun XY, Yu XL, Zhu J, Li LJ, Zhang L, Huang YR, Liu DQ, Ji M, Sun X, Zhang LX, Zhou WW, Zhang D, Jiao J, Liu RT. Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer's disease-like mouse model. Signal Transduct Target Ther. 2023 Jan 25;8(1):30. PubMed.
Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, Hyman BT. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci. 2002 Sep 15;22(18):7873-8. PubMed.
Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hyman BT, Bacskai BJ. A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis. 2007 Dec;28(3):286-92. PubMed.
Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci. 2003 Sep 17;23(24):8532-8. PubMed.
Baligács N, Albertini G, Borrie SC, Serneels L, Pridans C, Balusu S, De Strooper B. Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer's Disease. Nat Commun. 2024 Dec 5;15(1):10634. PubMed.
Mancuso R, Fattorelli N, Martinez-Muriana A, Davis E, Wolfs L, Van Den Daele J, Geric I, Premereur J, Polanco P, Bijnens B, Preman P, Serneels L, Poovathingal S, Balusu S, Verfaillie C, Fiers M, De Strooper B. Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology. Nat Neurosci. 2024 May;27(5):886-900. Epub 2024 Mar 27 PubMed.
Mancuso R, Van Den Daele J, Fattorelli N, Wolfs L, Balusu S, Burton O, Liston A, Sierksma A, Fourne Y, Poovathingal S, Arranz-Mendiguren A, Sala Frigerio C, Claes C, Serneels L, Theys T, Perry VH, Verfaillie C, Fiers M, De Strooper B. Stem-cell-derived human microglia transplanted in mouse brain to study human disease. Nat Neurosci. 2019 Dec;22(12):2111-2116. Epub 2019 Oct 28 PubMed.
Washington University School of Medicine
This exciting study explores the role of microglia in immune-mediated clearing of Aβ plaques in AD. The study integrated spatial transcriptomics, proteogenomics, and scRNA-Seq to analyze postmortem brain tissues from AD patients who received active or passive Aβ immunization, along with proper respective controls. Through extensive bioinformatics analyses, the authors identified specific microglial phenotypes in response to different treatment approaches, pointing to distinct cell states associated with Aβ plaque clearance in a brain-region-specific manner. Regional alterations of transcriptomic landscapes highlighted the upregulation of TREM2 and ApoE across therapeutics, while also unveiling divergent downstream responses, such as metabolic changes, complement regulation, and IL-2-STAT5 signaling. These correlated to different extents with Aβ removal. These findings add valuable knowledge on how microglia interact with, respond to, and potentially modulate AD therapeutics that target Aβ plaque removal.…More
In a broader sense, this study pinpointed the intersection of neurodegenerative disease with immunological change due to disease-modulating treatment, by examining the interplay of microglia with either active or passive Aβ immunization. Given the field’s longstanding interest in deciphering the role of microglia in AD pathophysiology, this manuscript added subtle characterizations from a bioinformatics standpoint. It identified distinct microglial states associated with effective plaque clearance, and distinct spatial correlations given the variable levels of regional brain pathology in AD.
The findings reinforce a growing consensus on the gene expression profile of DAM microglia, which includes such genes as TREM2, ApoE, and SPP1. They also suggest new genetic and molecular pathways, such as complement activation and IL-2-STAT5 signaling, to better our understanding of how microglia mediate the brain's response to Aβ immunotherapies. From an immunotherapy development standpoint, this study characterized microglia subtypes and states that are spatially distinct, paving the way for more precise treatment strategies and future efforts to modulate microglial functions in brain health and disease.
The overall approach provided a reliable methodology for the field to examine other cell types, and microenvironments of affected brain regions, to uncover new cellular and molecular mechanisms for various diseases, immunological responses, and contexts.
—Alexander Liu of Washington University of St. Louis is the co-author of this comment.
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