Single-cell and spatial multi-omics for understanding the pathogenesis of Alzheimer’s disease

AD is a slowly progressive and ultimately fatal neurodegenerative disorder, a leading cause of dementia, that causes degeneration of neurons and their connections in parts of the brain involved in memory. The symptoms are impairments in thinking, memory, reasoning, cognitive function and behavior known as dementia. Other diseases and conditions can also cause dementia, and AD is the most common cause of dementia in the elderly. AD is not a normal part of aging. It is the result of complex changes in the brain that begin years before symptoms appear, leading to loss of brain cells and connections.A hallmark of AD is the phosphorylated protein tau amyloid and neurofibrillary tangles is the presence of plaque. A large body of evidence implicates neuroinflammation, multiple systemic complications, in the pathology of AD.

Since AD ​​was first described in the early 1900s, clinicians and scientists around the world have sought to develop preventive, halting, and ultimately curative approaches to this most devastating disease. He has devoted his career to researching the pathophysiology of common diseases. The pathophysiology of AD involves neuron-glia interactions, corroborated by transcriptome and epigenome analyzes revealing downregulation of neuronal function and upregulation of innate immune responses in the AD brain. There are currently several FDA-approved tools that can be used where applicable to aid in the diagnosis of AD symptoms (brain imaging), while other new biomarkers show promise but are still under investigation (blood testing, genetic risk profiling).

Drugs exist, but if administered early, they may help treat early-stage AD symptoms and improve a person’s quality of life. Most recently, two pharmaceutical companies announced encouraging results from clinical trials in AD patients.A monoclonal antibody treatment called lecanemab reduced cognitive decline in people with early-stage disease by 27% compared to a placebo group after a year and a half. high risk of Alzheimer’s disease More than non-Hispanic whites, researchers don’t fully understand why. There is no one-size-fits-all drug to stop or reverse AD.

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The molecular and cellular mechanisms of AD are not fully understood. Typically, when scientists studied gene expression in the brain, they mashed up the tissues and obtained average measurements from the mixture. Such ‘bulk’ measurements are difficult to interpret, especially in small numbers of cell types, and the gene expression signals derived from individual cell types are lost. Numerous studies using bulk RNA-seq analysis have revealed dysfunctional neuronal and/or innate immune responses, which entangle the heterogeneity of different disease subtypes and differential responses between cell types. I can’t. Characterization of heterogeneity in brain regions important for learning and memory. Areas first affected in Alzheimer’s disease.

single cell genomics

Even within a single brain region, there are significant differences in the morphology, connectivity and electrophysical properties of individual neurons. An important step in understanding the basic building blocks of the nervous system is the systematic classification of individual neurons. To classify cells at the molecular level, gene expression must be assessed at single-cell resolution. Today’s high-throughput techniques such as single-cell and spatial multi-omics are revolutionizing neurological research with single-cell level resolution.

Collectively demonstrating how gene expression is regulated within individual cell types and specific anatomical regions of the brain at early stages of AD requires profiling tens of thousands of individual cells and It is important for studying the cellular heterogeneity of the brain by capturing molecules and cells. Identification of AD basis and novel therapeutic targets.

Figure 2: Multi-omics integration from a single brain (Image credit: 10x Genomics)

Overview

Gain an overview of cell-type-specific contributions to pathogenesis, map anatomical protein accumulation in the brain during disease progression, and understand the relationship between abnormal protein accumulation and cellular phenotyping at an early stage is very important to save people from this terrible disease..

Chromium Single Cell Multiome ATAC (Assay for Transposase-Accessible Chromatin) + Gene Expression (multi-team assay) to profile open chromatin and gene expression from the same cells and Visium Spatial Gene Expression for FFPE (Visium for FFPE) and using immunofluorescence (IF), which combines transcriptome-wide spatial analysis and immunofluorescent protein detection, can help extract intrinsic neuropathies shared among different conditions.

Multidimensional datasets obtained through single-cell genomics approaches will have a major impact on biological research and clinical pathology. The introduction and expansion of single-cell technology will greatly improve the diagnosis and treatment of patients worldwide.

References

1. 1. www.alzheimers.gov
2. 2. Liu-Lin Xiong et al., Single-cell RNA sequencing reveals B-cell-associated molecular biomarkers for Alzheimer’s disease, Nature, 2021
3. 3. Application Note: Identification of Alzheimer’s Disease Markers by Single Cell and Spatial Multi-omics, 10xgenomics.com/rs/446-PBO-704/images/10x_App-Note_Alzheimers_Letter_Digital.pdf
4. 4. Science Insider, https://www.science.org/content/article/five-big-questions-about-new-alzheimer-s-treatment
5. 5. National Institute of Aging: Alzheimer’s Fact Sheet
6. 6. Vinay CG, Project report on Alzheimer’s disease and its treatment. Nano Science and Technology Consortium, 2013

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