Good news!
"Researchers have for the first time identified degeneration-associated “molecular markers” – observable changes in cells and their gene-regulating networks – that are shared by several forms of dementia that affect different regions of the brain. Critically, the UCLA-led research ... also identified markers specific to different forms of dementia. The combined findings represent a potential paradigm shift in the search for causes, treatments and cures. ...
They performed single-cell genomic analysis on more than 1 million cells to identify distinct and shared molecular markers in three related conditions: Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy. In addition to validating changes previously observed in Alzheimer’s, they identify dozens of cell types whose changes are shared across multiple dementias and several cell types whose changes in disease were specific to a single disorder, many of which had not been previously identified. ...
The researchers:
- Identified unique changes specific to Alzheimer’s disease and demonstrated that several findings in Alzheimer’s were also observed across the other disorders, identifying targets for therapeutic development.
- Found that “cellular resilience programs” – molecular mechanisms that support cells in response to injury – activated or failed differently, when comparing the same cell types across disorders.
- Were surprised to discover that each of the three disorders had changes in cells of the primary visual cortex – the area of the brain that processes visual information and which was thought to be unaffected by dementia. In progressive supranuclear palsy, this discovery revealed previously unknown changes in brain cells called astrocytes.
- Identified specific changes in the expression of certain tau-related genes and others in progressive supranuclear palsy. These appear to correlate with the unique pattern of brain cell degeneration that is observed in progressive supranuclear palsy.
..."
From the highlights and abstract:
"Highlights
• Perform comparative genomic analysis of AD, bvFTD, and PSP at the single-cell level
• Pinpoint markers and candidate drivers of selective neuronal vulnerability in dementia
• Identify disorder-specific microglia, astrocyte, and oligodendrocyte glial-immune states
• Causal genetic risk impacts disorder-specific gene regulatory networks and cells
Summary
The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states."
Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics (no public access)
Graphical abstract
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