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Early Alzheimer's disease pathology in human cortex is associated with a transient phase of distinct cell states. | LitMetric

AI Article Synopsis

  • - Researchers created a single-nucleus atlas from living individuals with Alzheimer's disease to study cellular changes that occur at early stages of the illness.
  • - They identified a specific response in the brain called the Early Cortical Amyloid Response, characterized by hyperactive neurons and the loss of certain inhibitory neurons, along with increased neuroinflammation from microglia.
  • - Their findings help establish a framework for addressing issues like circuit dysfunction and amyloid production early in the development of Alzheimer's disease.

Article Abstract

Cellular perturbations underlying Alzheimer's disease are primarily studied in human postmortem samples and model organisms. Here we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of Alzheimer's disease pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the Early Cortical Amyloid Response-were prominent in neurons, wherein we identified a transient state of hyperactivity preceding loss of excitatory neurons, which correlated with the selective loss of layer 1 inhibitory neurons. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathological burden increased. Lastly, both oligodendrocytes and pyramidal neurons upregulated genes associated with amyloid beta production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10274680PMC
http://dx.doi.org/10.1101/2023.06.03.543569DOI Listing

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