Examining Human Brain Cell Changes in the Early Stages of Alzheimer's Disease
Prevention is both better than a cure and easier to achieve than a cure. Intervening early, prior to evident clinical symptoms of disease, is always desirable. This is challenging in the case of Alzheimer's disease because (a) there is little access to human brain tissue from people in the early stages of the condition, for ethical and regulatory reasons, and (b) Alzheimer's doesn't naturally occur in mice and other readily available mammalian species, so animal models of Alzheimer's are highly artificial, embodying assumptions about which disease processes are important. In this context, one can only learn from human brains. Here, researchers report on the results of a rare opportunity to study brain tissue samples from patients with early stage Alzheimer's disease.
Most Alzheimer's disease research on human brain tissue has studied postmortem samples, making it difficult for scientists to discern the earliest events in the brain that might have triggered the buildup of plaques and the death of neurons. Knowing the molecular changes in neurons, glia, and other brain cells around plaques during the early phases of the disease could help scientists design treatments that work best when given early.
Researchers have now 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 brain tissue samples were obtained from normal pressure hydrocephalus (NPH) patients during routine surgeries to reduce excess brain fluid. 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. A better understanding of how these cells spur the growth of plaques could one day help researchers identify new targets for Alzheimer's drugs.