Scientists reveal cellular changes unique to early Alzheimer’s disease in living tissue

Good news! The source of the samples is a bit unusual as well as odd and makes you wonder why this was not done before.

"Most Alzheimer’s disease research on human brain tissue has studied postmortem samples  ...

Now, in a study appearing ... has analyzed an assembly of rare brain tissue samples from 52 living patients with varying degrees of other Alzheimer’s-related changes in the brain — including 17 individuals who were later clinically diagnosed with the disease. The scientists identified a suite of changes in cells unique to the early stages of Alzheimer’s, including some not seen before in animal studies.

The team discovered a brief hyperactive state in a specific group of neurons that was associated with their death in later stages of the disease, and also increased inflammatory processes in immune cells called microglia as the disease progressed. Neurons are thought to produce the plaque-forming protein called amyloid beta, and the researchers found evidence for this in their data. They also found for the first time that another brain cell type, oligodendrocytes, which produce insulating sheaths around nerve fibers in the brain, may also contribute to plaque formation.  ...

The study is a result of close collaboration with Ville Leinonen, a neurosurgeon and professor from the University of Eastern Finland who has spent more than a decade collecting and studying brain tissue samples from patients who underwent routine surgeries for other neurological conditions and agreed to provide a small amount of brain tissue and other samples for research. ..."

From the highlights and abstract:

"Highlights

• Single-nucleus profiling of human cortex biopsies uncovers amyloid-associated states

• Upper-layer pyramidal neurons show hyperactivity prior to degeneration

• Microglial states correlate with pathological and clinical progression

• Signatures of amyloid production identified in both neurons and oligodendrocytes

Summary

Cellular perturbations underlying Alzheimer’s disease (AD) 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 AD 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 transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with β-amyloid 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."

Scientists reveal cellular changes unique to early Alzheimer’s disease | Broad Institute A study of brain tissue from living adults provides a rare look into the earliest stages of the neurodegenerative disease and highlights cell types involved in plaque production.

Early Alzheimer’s disease pathology in human cortex involves transient cell states (open access)

Graphical abstract