Keeping Microglia from Multiplying Puts the Brakes on Alzheimer’s at Early Stages

Microglia are the primary resident macrophages in the brain, endowed with the responsibility of engulfing pathogens and other aberrant material.

Rapid multiplication of a small group of microglial cells in response to the early accumulation of toxic amyloid accelerates the progression of Alzheimer’s disease.

After an early burst of cell division in disease-associated microglia (DAM), they stop dividing, going into a state of “replicative senescence,” marked by metabolic dysfunction that drives a damaging inflammatory milieu, a new study shows.

Keeping DAM from dividing, the scientists showed, prevents microglial senescence and decreases amyloid accumulation and synaptic damage—the hallmarks of Alzheimer’s pathology.

The study, “Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology,” was published in the journal Cell Reports, and probes into the long-term impact of the early and prolonged microglial cell division characteristic of Alzheimer’s disease. The results reported provide insights into how Alzheimer’s disease begins, and how its progression could be restricted.

“We have previously established that microglia respond to toxic amyloid by proliferating, which is part of their function as immune cells, they are trying to contain a foreign protein,” said Diego Gomez-Nicola, PhD, associate professor in neuroimmunology at the University of Southampton, U.K. “However, this is the first time we have seen the long-term consequences of this proliferation on the cells, and the impact for the development of the disease.”

The scientists showed early and continued microglial cell cycling in a mouse model of Alzheimer’s disease engenders a unique transcriptomic signature that promotes replicative senescence where the expression of a gene called beta-galactosidase increases and protective telomeres caps at the ends of chromosomes shorten.

These findings indicate excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early amyloid beta pathology in Alzheimer’s disease.

Gomez-Nicola said: “These findings have pinpointed a small group of microglia that have a profound influence on the rate at which Alzheimer’s disease accelerates. As well as providing scientists with more insight into the starting point of the disease, it will enable future research and drug discovery efforts to be refined to target these senescent cells specifically, and hopefully expedite further breakthroughs in the search for effective treatments.”