Early Alzheimer’s disease pathology in human cortex is associated with a transient phase of distinct cell states

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.

A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer’s disease

“…However, instead of systematically selecting compounds/modulators following a rational design strategy 12 , this effort reversed the approach by exposing iMG to selected CNS- substrates, perturbing their transcriptome. The authors subsequently correlated the induced subtypes with previously described human microglial subtypes derived from snRNAseq datasets 50 . While this approach is interesting and yielded intriguing insights, it is limited by the variability of the preparation of some of the stimulants (such as synaptic preparations) and the lack of direct translation to therapeutic development.…”

Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer’s disease

“…In Alzheimer's disease (AD) and its mouse models, amyloid-β (Aβ) production has primarily been attributed to excitatory neurons (ExNs) 1 , despite emerging evidence that other cell types, such as inhibitory interneurons or glial cells, might contribute to Aβ production 2,3 . Cultured oligodendrocytes (OLs) are capable of generating detectable levels of Aβ in vitro [4][5][6] . Since OL lineage cells are abundantly present in both gray and white matter (WM) and myelin alterations have been implicated in AD [7][8][9][10] , we asked whether OLs would directly contribute to Aβ plaque burden in vivo.…”