Description

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/. Brain autopsied amples from Knight-ADRC. After data cleaning and quality control, 11,166 microglia nuclei remained for downstream analyses.

The study is published in the manuscript “Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy”, By  Da Mesquita et al, Nature 2021 (https://pubmed.ncbi.nlm.nih.gov/33911285/).

Data Releases:
1. The first release (June 1, 2021) includes sample meta data, study-wide unique barcodes of nuclei, gene expression data, and sample consent information.
2. The second release (November 23, 2021) has added single-nuclei RNA-seq sequence files, code files, genotypes for EQTL analysis, and phenotype files.

Sample Summary per Data Type

Sample SetAccessionData TypeNumber of Samples
Microglia expression profiles in ADsnd10021Single Cell RNA Sequencingn = 44

Available Filesets

NameAccessionLatest ReleaseDescription
Microglia expression profiles in ADfsa000007NG00108.v2Microglia profile, subject, and phenotype data
Microglia expression profiles in AD - GWASfsa000015NG00108.v2GWAS data
Microglia expression profiles in AD - Single-nuclei RNA-seq Sequencefsa000016NG00108.v2Single-nuclei RNA-seq Sequence data

View the File Manifest for a full list of files released in this dataset.

The microglia profile of the Parietal lobe of 44 donors from the Knight ADRC were sequenced using 10X genomics 3’ Chemistry v3 (10,000 nuclei per donor, 50,000 reads per nuclei), and aligned to the precursor mRNA reference (build GRCh38).

Sample SetAccessionNumber of Subjects
Microglia expression profiles in ADsnd10021n = 44
Consent LevelNumber of Subjects
DS-ADRD-IRB-PUBn = 44

Visit the Data Use Limitations page for definitions of the consent levels above.

Total number of approved DARs: 1
  • Investigator:
    Pendergrass, Sarah
    Institution:
    Genentech
    Project Title:
    Genetic Analyses Using Data from the Alzheimer’s Disease Sequencing Project (ADSP) and related studies
    Date of Approval:
    July 16, 2021
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    The purpose of our study is to identify novel genetic factors associated with Alzheimer’s Disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). This includes identifying genetic factors associated with the risk of these conditions, as well as genetic risk factors associated with age-at-onset (AAO) for these conditions. We will also evaluate genetic associations with sub-phenotypes individuals have within these broad disease categories, such as their Braak staging results which provide insights into the level of severity of Alzheimer’s. Thus we are requesting access to the set of genomic Whole Exome and Whole Genome Sequences (WES and WGS) have just been released through the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (DSS NIAGADS). The findings from our genetic association testing have the potential for identification of new therapeutic targets for Alzheimer's Disease, CBD, and PSP. The findings from our studies also have the potential for identification of genetic and phenotypic biomarkers that will be beneficial for subsetting patients in new ways. We will use standard genetic epidemiological methods to handle the WGS and WES data. We will also analyze cell type-specific expression differences in AD to identify biomarkers and disease pathways using standard gene expression analysis methods currently in use.All data will remain anonymized and securely stored, and only those listed on our application and their staff will have access to these data. We will not share any of the individual level data outside of Genentech nor beyond the researchers on our application. We will adhere to all data use agreement stipulations through the DSS NIAGADS. We have a secure computational environment called Rosalind within Genentech where we will use these data. We have IT security staff that constantly monitor all our research computing, assuring safety and privacy of all of our stored data. We will not collaborate with researchers at other institutions.
    Non-Technical Research Use Statement:
    Genetic variation and gene expression data allows us to understand more of the genetic contribution to risk and protection from diseases such as Alzheimer’s and dementia. This information also allows us to identify important biological contributors to disease for developing effective treatment strategies, and identifying groups of individuals that would benefit most from new treatments. Our exploration of this relationship between genotype, disease traits, gene expression, and outcomes, through these datasets will allow us to pursue important new findings for disease treatment.

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

Use the study-specific acknowledgement statements below (as applicable):

For investigators using any data from this dataset:

Please cite/reference the use of NIAGADS data by including the accession NG00108.

For investigators using KnightADRC (sa000008) data:

This work 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. 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

Da Mesquita, Sandro et al. “Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.” Nature vol. 593,7858 (2021): 255-260. doi:10.1038/s41586-021-03489-0
Pub Med Link