Comment on New Multiomic Atlas to Decode the Brain’s Blood Vessels posted on ALZFORUM
ALZFORUM Comment by Md Rezaul Islam, PhD and Li-Huei Tsai, PhD
In this study, Reid, Yang, and colleagues present MultiVINE-Seq, a multiomic, single-nucleus profiling method that captures paired transcriptomic and epigenomic data from human brain vascular, perivascular, and immune cells. This study represents the first dataset of its kind with such a rich multiomics profile of non-parenchymal cells, surpassing prior reports by several-hundred-fold and enabling the authors to map thousands of GWAS noncoding disease risk variants to specific vascular and immune cell regulatory regions.
By mapping these noncoding risk variants to the captured cell types, the authors identified disease-specific, cell-type enrichment patterns. For example, they observed differential associations of noncoding risk variants between cerebrovascular and neurodegenerative diseases: risk genes were primarily enriched in fibroblasts for cerebrovascular disease, whereas they were predominantly associated with perivascular macrophages and microglia in the context of neurodegenerative diseases.
The authors also identified several active AD risk variants enriched in infiltrating T cells, and brain endothelial cells. One notable example is a lead AD risk variant that enhances PTK2B expression in brain T cells, providing genetic evidence for the involvement of adaptive immunity in AD pathogenesis.
Additionally, they discovered that two other active AD-associated risk variants, enriched specifically in brain endothelial cells, are located in chromatin regions that are strongly connected to the CASS4 gene locus. These genetic regions may act as upstream regulatory elements influencing the expression of CASS4 in brain endothelial cells. CASS4, a scaffolding protein involved in integrin-mediated adhesion and known for its role in cellular responses to environmental changes and immune activation (Tikhmyanova et al., 2010), may contribute to maintaining blood-brain barrier integrity and modulating immune cell recruitment during neuroinflammation. These findings warrant further investigation to better understand the specific role of CASS4 in endothelial cells during inflammation and neurodegeneration.
The publicly available MultiVINE-Seq dataset will serve as a valuable resource for future efforts aimed at disentangling the non-neuronal drivers of AD. This dataset can also be further integrated with existing human brain atlases, including our own (Sun et al., 2023), to prioritize vascular gene targets for functional validation—such as using stem cell-based human blood-brain barrier models (Blanchard et al., 2020; Ahn and Kim, 2021) and animal models to assess their roles in vascular integrity during neuroinflammation and dementia.
References:
Blanchard JW, Bula M, Davila-Velderrain J, Akay LA, Zhu L, Frank A, Victor MB, Bonner JM, Mathys H, Lin YT, Ko T, Bennett DA, Cam HP, Kellis M, Tsai LH. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat Med. 2020 Jun;26(6):952-963. Epub 2020 Jun 8PubMed. Correction.
Ahn SI, Kim Y. Human Blood-Brain Barrier on a Chip: Featuring Unique Multicellular Cooperation in Pathophysiology. Trends Biotechnol. 2021 Aug;39(8):749-752. Epub 2021 Feb 15 PubMed.
Sun N, Akay LA, Murdock MH, Park Y, Galiana-Melendez F, Bubnys A, Galani K, Mathys H, Jiang X, Ng AP, Bennett DA, Tsai LH, Kellis M. Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer's disease. Nat Neurosci. 2023 Jun;26(6):970-982. PubMed. Correction.
Tikhmyanova N, Little JL, Golemis EA. CAS proteins in normal and pathological cell growth control. Cell Mol Life Sci. 2010 Apr;67(7):1025-48. PubMed.
