Abstract
Alzheimer’s disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.
| Original language | English (US) |
|---|---|
| Article number | 278 |
| Pages (from-to) | 1604-1616 |
| Number of pages | 13 |
| Journal | Nature Medicine |
| Volume | 31 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2025 |
Funding
We thank D. Bennett (Rush University) for early access to the ROSMAP snRNA-seq dataset. We thank S. H. -Y. Chou, N. Reish, D. Chatterjee and D. Krainc (Northwestern University) for helpful discussion. We also thank B. Veire (10x Genomics) for assistance with spatial proteogenomics. We also thank the staff members of the Stanford and Northwestern Alzheimer\u2019s Disease Research Centers for their assistance acquiring nAD and NND control brain tissues under NIH P30AG066515 and P30AG072977, respectively. Finally, we thank D. Kirchenbuechler and C. M. Wai (Northwestern University) for their support. Figs. 1a,b, 3a\u2013c and 4a and Extended Data Fig. 5k were created using BioRender.com. ROSMAP is supported by P30AG10161, P30AG72975, R01 AG15819, R01 AG17917, U01AG46152 and U01AG61356. ROSMAP resources can be requested at https://www.radc.rush.edu/ and https://www.synapse.org/. The collection of the AN1792-immunized cases was supported by the Medical Research Council (G0501033) and Alzheimer\u2019s Research UK (ART/PG2006/4, ART-EXT2010-1) with the tissue samples obtained from the University Hospital Southampton NHS Foundation Trust as part of BRAIN UK, which is supported by Brain Tumour Research and has been established with the support of the British Neuropathological Society and the Medical Research Council. This work was further supported by Northwestern University\u2019s Center for Advanced Microscopy and a Cancer Center Support Grant (NCI CA060553) and NUSeq Core Facility, Alzheimer Nederland Impulssubsidie grant WE.06-2023-03 (to L.v.O.), Alzheimer Nederland Early Career grant WE.03-2023-08 (to L.v.O.), National Institute of Neurologic Disease and Stroke K99/R00 Pathway to Independence award NS112458 (to D.G.), Bright Focus Foundation award A2023003S (to D.G.), Alzheimer\u2019s Association 23AARG-1026607 (to D.G.) and National Institute on Aging R01AG078713 (D.G.). We thank D. Bennett (Rush University) for early access to the ROSMAP snRNA-seq dataset. We thank S. H. -Y. Chou, N. Reish, D. Chatterjee and D. Krainc (Northwestern University) for helpful discussion. We also thank B. Veire (10x Genomics) for assistance with spatial proteogenomics. We also thank the staff members of the Stanford and Northwestern Alzheimer\u2019s Disease Research Centers for their assistance acquiring nAD and NND control brain tissues under NIH P30AG066515 and P30AG072977, respectively. Finally, we thank D. Kirchenbuechler and C. M. Wai (Northwestern University) for their support. Figs. , and and Extended Data Fig. were created using BioRender.com . ROSMAP is supported by P30AG10161, P30AG72975, R01\u2009AG15819, R01\u2009AG17917, U01AG46152 and U01AG61356. ROSMAP resources can be requested at https://www.radc.rush.edu/ and https://www.synapse.org/ . The collection of the AN1792-immunized cases was supported by the Medical Research Council (G0501033) and Alzheimer\u2019s Research UK (ART/PG2006/4, ART-EXT2010-1) with the tissue samples obtained from the University Hospital Southampton NHS Foundation Trust as part of BRAIN UK, which is supported by Brain Tumour Research and has been established with the support of the British Neuropathological Society and the Medical Research Council. This work was further supported by Northwestern University\u2019s Center for Advanced Microscopy and a Cancer Center Support Grant (NCI CA060553) and NUSeq Core Facility, Alzheimer Nederland Impulssubsidie grant WE.06-2023-03 (to L.v.O.), Alzheimer Nederland Early Career grant WE.03-2023-08 (to L.v.O.), National Institute of Neurologic Disease and Stroke K99/R00 Pathway to Independence award NS112458 (to D.G.), Bright Focus Foundation award A2023003S (to D.G.), Alzheimer\u2019s Association 23AARG-1026607 (to D.G.) and National Institute on Aging R01AG078713 (D.G.).
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology