The data for this dataset is available on NIAGADS DSS: https://dss.niagads.org/datasets/ng00108/
Alzheimer’s disease (AD) is the most prevalent cause of dementia. While there is no effective treatment for AD, a growing body of evidence points to passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) as a promising therapeutic strategy. Meningeal lymphatic drainage plays an important role in Aβ accumulation in the brain, yet it is unknown if or how modulating meningeal lymphatic function can influence the outcome of anti-Aβ immunotherapy in AD. Analysis of the meninges of middle-aged AD transgenic 5xFAD mice revealed an accelerated deterioration of lymphatic vasculature. Ablation of meningeal lymphatic vessels in adult 5xFAD mice exacerbated Aβ deposition, microgliosis and affected neurovascular activation, increasing the amount of Aβ load and aggravating behavioral deficits following passive immunotherapy. On the contrary, therapeutic delivery of vascular endothelial growth factor C improved Aβ clearance by monoclonal antibodies and tuned hippocampal function in aged AD transgenic mice. Furthermore, we present a set of AD-associated genes that are highly expressed by meningeal lymphatic endothelial cells and correlate with altered levels of Aβ42 in the cerebrospinal fluid as well. We sought to investigate the microglial pathways affected in AD in human brains. To do so, we generated single-nuclei RNA-seq (snRNA-seq) from the parietal cortex from the Knight ADRC. We generated snRNAseq (10X chemistry v3) for AD, presymptomatic (ATN+ with cognition intact) and controls with none or neglectable AD pathology. After data cleaning and quality control,11,166 microglia nuclei remained for clustering and downstream analyses. A significant overlap was found between the gene signature of microglia from 5xFAD mice with dysfunctional meningeal lymphatics and the transcriptional profile of activated microglia from the human AD brain. Overall, our data demonstrates that impaired meningeal lymphatic drainage impacts the microglial inflammatory response in AD and that enhancement of meningeal lymphatics, alone or combined with potential passive immunotherapies, could lead to better clinical outcomes.
Single nuclei RNA-seq (10X chemistry v3) was generated from the parietal lobe as described in https://pubmed.ncbi.nlm.nih.gov/33911285/. After data cleaning and quality control, 11,166 microglia nuclei remained for downstream analyses.
The KnightADRC (sa000008) study was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501 and R01AG057777). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine.
We thank the contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Members of the National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD NCRAD) Family Study Group include the following: Richard Mayeux, MD, MSc; Martin Farlow, MD; Tatiana Foroud, PhD; Kelley Faber, MS; Bradley F. Boeve, MD; Neill R. Graff-Radford, MD; David A. Bennett, MD; Robert A. Sweet, MD; Roger Rosenberg, MD; Thomas D. Bird, MD; Carlos Cruchaga, PhD; and Jeremy M. Silverman, PhD.
Grant Funding for the Profiling microglia expression profiles in AD using single-nuclei RNA-seq dataset:
R56-AG067764- Harari, Cruchaga, Karch
P30AG066444- Harari, Cruchaga