Key mechanisms in asymptomatic Alzheimer’s disease brains may protect against cognitive decline
Indiana University School of Medicine researchers are studying the brains of a subset of people with asymptomatic Alzheimer's disease who, despite having amyloid plaque and tau buildup — the two hallmarks of Alzheimer's — postmortem, experienced no diagnosable dementia symptoms while they were living.
They have uncovered key mechanisms that may protect against cognitive decline in Alzheimer's disease.
The team of researchers in the Stark Neurosciences Research Institute at the IU School of Medicine, led by Nur Jury-Garfe, PhD, assistant research professor of anatomy, cell biology and physiology, and Cristian Lasagna-Reeves, PhD, associate professor of anatomy, cell biology and physiology, published their findings in Acta Neuropathologica.
In asymptomatic Alzheimer’s disease cases, microglia — the brain's immune cells — are more abundant around amyloid plaques and display enhanced actin-based motility proteins, which drive cell and microglia movement. Microglia act as the first line of defense in the brain, "cleaning up" viruses, toxic materials and damaged neurons.
Jury-Garfe said actin-based motility proteins are like "tiny engines" that help microglia respond to damage caused by harmful proteins like amyloid plaques. In later stages of the disease, however, microglia can become less effective and even harmful for reasons not fully known.
"When motility proteins in microglia function well, they help cells quickly reach and surround plaques, potentially preventing further damage," Jury-Garfe said. "This enhanced movement in asymptomatic cases may be crucial for protecting the brain and slowing the progression of Alzheimer's disease symptoms. It’s like having a highly efficient cleaning team that can respond quickly, keeping things under control before they get worse."
Additionally, Jury-Garfe said the team's research revealed that tau seed capability significantly reduced in asymptomatic Alzheimer's disease brains, which was an unexpected finding from the research team. The tau seed is the species of the protein tau that propagates in the brain, moving from neuron to neuron, creating toxic soluble tau aggregates and producing neurodegeneration.
"Our study highlights the dual role of microglia in both contributing to and protecting against amyloid plaque toxicity and the formation of toxic soluble tau aggregates," Jury-Garfe said. "By understanding how increased actin-based motility proteins support resilience in asymptomatic Alzheimer’s disease cases, we can potentially uncover therapeutic strategies to enhance microglial function and mitigate Alzheimer’s disease pathology."
