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Single-cell multi-omic and multi-region atlas of the Human Alzheimer's Disease Brain

ABSTRACT: Alzheimer’s disease (AD) is the leading cause of dementia, driven by complex molecular alterations that disrupt neural and glial cell function. However, the precise epigenomic and chromatin regulatory changes underlying AD pathogenesis across different brain regions remain incompletely understood. To address this, we generated a comprehensive single-cell multi-omic atlas of the human AD brain. We profiled 11 AD donors and 9 age-matched healthy donors, spanning three key brain regions implicated in AD pathology: the visual cortex (VC), temporal cortex (TC), and prefrontal cortex (PFC). Using single-nucleus methylome sequencing (snmC-seq3) and joint profiling of chromatin conformation and DNA methylation (snm3C-seq), we obtained extensive datasets enabling integrated analysis of transcriptional regulation, epigenetic remodeling, and 3D genome architecture. This resource allowed us to characterize AD-associated alterations in DNA methylation at promoters, enhancers, and transposable elements, as well as their consequences on transcription factor motif accessibility. At the chromatin level, we identified disease-related changes in higher-order genome organization, including compartments, topologically associating domains (TADs), and loops. By comparing multiple cortical regions, we also uncovered regional heterogeneity within matched cell types, highlighting both shared and region-specific epigenetic signatures of AD. Together, this atlas provides a systematic, multi-region view of single-cell epigenomic landscapes in AD and offers insights into regulatory mechanisms underlying disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308132 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is a chronic ageing related neurodegenerative disease which is characterized by loss of synapses and neurons in the vulnerable brain regions. Expression perturbations of amyloid β (Aβ) and tau protein in the brain are two hallmarks of AD. Aβ is abnormally generated from amyloid precursor protein (APP) which is broadly distributed in different brain regions including the hippocampus and cortex. It is believed that increased Aβ expression plays a causative role in the early stage of AD pathology. Aβ protein interacts with the signaling pathways that control the phosphorylation of the microtubule-associated protein tau, which eventually disrupts the neuronal circuitry as well as network connectivity leading to neurodegenerative processes observed in AD. In addition, substantial molecular and neurodegenerative changes occur in the initial stage of AD even before the cognitive symptoms are evident, which makes the early diagnosis of AD vital to any timely disease stabilization and treatment. However, despite myriad efforts and substantial progress in the field to decipher the molecular mechanisms of disease onset and its progression, specific causes underlying AD pathology remain ill-defined. There is an urgent need to identify novel mechanism based interventional approaches that can stop, or slow down, the progression of AD. Therefore, it is important to improve the knowledge of the early AD and have a better understanding of the underlying molecular mechanisms induced by Aβ. In this study, we performed comparative quantitative proteomics on different brain regions of 2.5 months old APP/PS1 mice (hippocampus, frontal cortex, parietal cortex and cerebellum) in order to investigate the early stage impact of AD. Although over 5000 proteins were identified in all regions, the proteome response across regions was greatly varied. As expected, the greatest proteome perturbation was detected in the hippocampus and frontal cortex (AD-susceptible brain regions), compared to only 155 changed proteins in the cerebellum (less vulnerable region to AD). Increased expression of APP protein was identified in all brain regions. The expression of the majority of the other proteins between hippocampus and cortex areas was not similar, highlighting differential effects of the disease on different brain regions. A series of AD associated markers and pathways were identified as overexpressed in the hippocampus including glutamatergic synapse, GABAergic synapse, retrograde endocannabinoid signaling, long-term potentiation, and calcium signaling. In contrast, the expression of same proteins and pathways was negatively regulated in frontal and parietal cortex regions. Additionally, an increased expression of proteins associated with the oxidative phosphorylation pathway in hippocampus was not evident in the two cortices. Interestingly, an increased expression of proteins involved with myelination, neurofilament cytoskeleton organization, and glutathione metabolism was identified in cortex areas, while these were reduced in the hippocampus. The results obtained from this study highlight important information on brain region specific protein expression changes occurring in the early stages of AD.

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Single-cell multi-omic and multi-region atlas of the Human Alzheimer's Disease Brain

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