Alzheimer's disease (AD) is the most common degenerative disease of the central nervous system worldwide, clinically manifested by a gradual loss of cognitive function and the ability to live daily living, accompanied by psychobehavioral abnormalities and personality changes. As the most common type of dementia, AD is one of the most disabling and burdensome diseases worldwide. Age is the most important risk factor for AD, and the prevalence increases 1-fold for every 5 years of age in people over 65 years of age. It is worth noting that China's AD patients rank first in the world, and with the extension of the average life expectancy of the mainland population and the advent of the aging society, the mainland is entering a period of high incidence of AD. However, despite hundreds of years of research, the exact pathogenesis of AD remains unclear.
On September 28, 2023, Professor Li-Huei Tsai of the Massachusetts Institute of Technology published three research papers related to AD in the journal Cell, namely:
- “Human microglial state dynamics in Alzheimer’s disease progression“，
- ”Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology“,
- “Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology“。
Professor Cai Lihui's team analyzed the pathogenic mechanism of Alzheimer's disease from multiple angles at the cellular, genetic and mechanism levels, providing new insights for the prevention and treatment of AD!
Revealing the dynamics of microglial status during Alzheimer's disease progression
The different states of microglia influence neuroinflammation, neurodegeneration, and other central nervous system diseases, but the mechanisms are still poorly understood.
Cai's team revealed microglial state dynamics changes and mechanisms in AD disease progression by performing mononuclear transcriptome and epigenomic analysis on 443 human subjects and 194,000 mononuclear microglia with different Alzheimer's disease (AD) pathological phenotypes. The research paper Human microglial state dynamics in Alzheimer's disease progression was published in the journal Cell.
The study first identified 12 microglial transcriptional states, including homeostasis, inflammation, and lipid processing states of AD dysregulation, and 1542 AD differentially expressed genes (including microglial status and disease-stage specific alterations). Secondly, by integrating epigenome, transcriptome and motif information, the upstream regulators, gene regulatory networks, enhancer gene linkages, and microglial state transitions driven by transcription factors were inferred, and the regulatory network controlling microglial state transitions during AD progression was described. And in human ipsc-derived microglia-like cells, ectopic expression of predicted homeostatic activators can induce homeostatic features, however, activators that inhibit inflammation can block the progression of inflammation. The study revealed the diversity of microglia in different disease stages, disease stage changes in gene expression, and regulatory networks that control microglial state transitions during AD progression, providing new insights for the prevention and treatment of Alzheimer's disease!
Uncover new mechanisms by which neuronal DNA double-strand breaks cause genomic structural variation and 3D genomic disruption
Neuronal DNA double-strand breaks (DSBs) are early pathological markers of neurodegenerative diseases such as Alzheimer's disease (AD) and may disrupt genome integrity, but the mechanism of AD epigenetic alterations triggered by DSBs has been rarely reported.
Cai Lihui's team used postmortem prefrontal cortex autopsy samples of AD patients and brain tissue from CK-p25 mouse model to perform monocyte RNA sequencing (snRNA-seq) analysis, respectively, demonstrating that neuronal DSBs are the key pathological mechanism that disrupts genomic stability and 3D genomic structure in AD disease progression. The research paper, Neuronal DNA double-strand breaks, leads to genome structural variations and 3D genome disruption in neurodegeneration, was published in the journal Cell.
The study used snRNA-seq analysis in human postmortem prefrontal cortex samples and found that gene fusions were abundant in excitatory neurons with DNA damage repair and aging genetic signatures. In addition, in the CK-p25 mouse neurodegenerative model, it was also found that the accumulation of DSBs in neurons would lead to genome structural variation and gene fusion enrichment, and the frequency of DNA fragmentation of long transcripts and genes at high transcription levels was higher, and structural variation and gene fusion were more likely to occur, suggesting that the destruction of genome stability and 3D genome by DSBs in neurons is a key pathological factor that cannot be ignored in neurodegenerative diseases.
Single-cell atlas reveals correlations between high cognitive function, dementia, and pathological resilience to AD
Alzheimer's disease (AD) is the most common cause of dementia, but the molecular and cellular mechanisms behind cognitive impairment remain unclear.
Cai Lihui's team analyzed more than 2.3 million nuclei in the autopsy brain tissue of 427 AD patients with different degrees of pathology and cognitive impairment through monocytes RNA sequencing (snRNA-seq), and generated a complete cell transcriptome map of the prefrontal cortex of the elderly. The study identified AD pathologically associated alterations common between excitatory neuron subtypes, where the Cohesin complex and DNA damage response factors were synergistically elevated in excitatory neurons and oligodendrocytes, and identified genes and pathways associated with high cognitive function, dementia, and AD pathological resilience. In addition, through the analysis of somatostatin inhibitory neurons in the brain of AD patients, it was found that there were two types of suppressor neurons with high abundance in individuals who still maintained high cognitive function in their later years, suggesting the link between suppressor neurons and the pathological recovery ability of AD, which provides a potential therapy for the treatment of Alzheimer's disease! The research paper, Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology, was published in the journal Cell.
Bibliography:
- Sun et al., Human microglial state dynamics in Alzheimer’s disease progression, Cell (2023), https://doi.org/10.1016/j.cell.2023.08.037
- Mathys et al., Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology, Cell (2023), https://doi.org/10.1016/j.cell.2023.08.039
- Dileep et al., Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration, Cell (2023), https://doi.org/10.1016/j.cell.2023.08.038
In addition to the above three research papers, Manolis Kellis and Cai Lihui's team also published a resource-based data at the same time. The epigenome and transcriptome maps of 850,000 nuclei from the prefrontal cortex of 92 AD patients and AD-free patients were analyzed, and the brain regulatory group map was constructed, including epigenome maps, transcriptional regulators and other data.
Cover image for this issue of Cell
Compiled by Sherry (BrainNews Creative Team)
Proofreader: Simon (Brainnews Editorial Office)