Journal Article

Single-cell multiregion dissection of Alzheimer’s disease

Louderback, Kate, Tanzi, Rudolph E., Prokopenko, Dmitry, Mathys, Hansruedi, Bennett, David A., Band, Neil, James, Benjamin T., Abdelhady, Ghada, Jiang, Xueqiao, Babu, Sudhagar, Galani, Kyriaki, Galiana-Melendez, Fabiola, Kellis, Manolis, Mantero, Julio, Tsai, Li-Huei, Xia, Ziting, Boix, Carles A., Ng, Ayesha P., Akay, Leyla Anne, Davila-Velderrain, Jose

2024

Overview

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood 1 – 3 . Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology. A regional atlas of the ageing human brain—spanning six distinct anatomical regions from individuals with and without Alzheimer’s dementia—provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/32 / 38/39 / 631/208/199 / 631/378/1689/1283 / 631/378/340 / 64/60 / 82/51 / Aged, 80 and over / Aging - metabolism / Aging - pathology / Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Animals / Astrocytes / Astrocytes - classification / Astrocytes - cytology / Astrocytes - metabolism / Astrocytes - pathology / At risk populations / Autopsy / Biosynthesis / Brain / Brain - anatomy & histology / Brain - cytology / Brain - metabolism / Brain - pathology / Case-Control Studies / Choline / Choline - metabolism / Cognition - physiology / Cognitive ability / Dementia / Dementia disorders / Female / Gene Expression Profiling / Gene Regulatory Networks / Humanities and Social Sciences / Humans / Interneurons - classification / Interneurons - cytology / Interneurons - metabolism / Interneurons - pathology / Localization / Male / Mice / Modules / multidisciplinary / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neural Inhibition / Neurodegenerative diseases / Neurons / Neurons - classification / Neurons - cytology / Neurons - metabolism / Neurons - pathology / Pathology / Polyamines / Polyamines - metabolism / Reelin Protein / Regional development / Resilience / Science / Science (multidisciplinary) / Signal Transduction / Single-Cell Analysis / Thalamus / Thalamus - cytology / Thalamus - metabolism / Thalamus - pathology / Transcriptome / Transcriptomics