Brain Inflammation Linked to Alzheimer's Risk Gene

A team of researchers has identified how the APOE4 protein, a major genetic risk factor for Alzheimer's disease, can negatively impact brain health. They found that APOE4 can induce microglia, the brain's immune cells, to cause harmful inflammation and the formation of harmful protein clumps. ()

The same microglia, in a brain without APOE4 protein, patrol for damage and clear away debris and harmful proteins. For the study, scientists at Gladstone Institutes in the US created a "chimeric" mice model for studying Alzheimer's. The mouse model not only carries human APOE genes, but the team also transplanted human neurons producing the APOE4 protein into the brains of mice. On removing microglia, they discovered that the APOE4 protein no longer triggered as many deposits of amyloid or tau -- two types of misfolded proteins that are hallmarks of Alzheimer's disease.

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APOE4 and Alzheimer's: A New Therapeutic Target

The findings, published in the journal Cell Stem Cell, suggest that drugs that can reduce levels of APOE4 in neurons or target microglia -- either by reducing the number of microglia or their level of inflammatory activity -- could be a promising strategy for slowing or preventing Alzheimer's disease progression in people with the APOE4 gene. Gladstone Senior Investigator Yadong Huang said that "drugs reducing microglia (in Alzheimer's patients) may eventually be useful in treating the disease".

Importantly, the team transplanted the neurons in the mice model, after the brain matured. This helped the researchers to mimic late-onset Alzheimer's disease. While it has been previously established that APOE4 leads to higher-than-usual levels of amyloid plaques and tau tangles in human brains, the new model confirmed with APOE4 neurons the number of both amyloid and tau deposits surge, as the mice aged.

Human neurons without the APOE gene altogether resulted in fewer tau aggregates and scattered amyloid deposits rather than dense, harmful aggregates, the researchers said. Further, using a drug the team selectively removed microglia from the brains of the chimeric mice.

This resulted in a significant decline in the levels of the amyloid and tau aggregates in mice with human APOE4 neurons. The decline indicates that APOE4 and microglia work together to drive key attributes of Alzheimer's disease. The team also found that the levels of inflammatory molecules in microglia increased when human neurons containing APOE4 and APOE3 were present.

Reference:

1. Linking APOE4/4 genotype to microglial lipid droplets and neurotoxicity in Alzheimer's disease - (https:www.aging-us.com/article/205776/text)

Source: IANS