On 10 October, Dr Yang Shi and colleagues published a paper in the Journal of Experimental Medicine showing that ApoE4 induces microglial activation in animal models of tauopathy and Alzheimer’s disease (AD), driving disease progression. This publication follows on from their 2017 Nature paper, which showed that ApoE4 exacerbates neuroinflammation and tau pathology independently of amyloid-β. Recent studies have provided major insights into how ApoE regulates neurodegeneration. In line with clinical studies showing that ApoE4 allele is a major genetic risk factor for AD, these studies identified a direct link between ApoE4 and the levels of tau protein in the brains of people with AD. Using animal models, scientists showed that the absence of ApoE was strongly neuroprotective, preventing neurodegeneration even when pathological tau proteins were present. Intriguingly, a marked elevation in microglial activation was observed in animals with an ApoE4 genotype, suggesting that ApoE may also play an important role in AD-associated neuroinflammation. In their current publication, Dr Shi and colleagues hoped to shine a spotlight on neuroinflammation, aiming to identify exactly how ApoE drives AD progression through its effects on microglia in the brain.
To answer this question, the researchers used mouse models of AD that had been genetically modified to produce large amounts of pathological, phosphorylated tau proteins (P301S mice). On this tauopathy background, Dr Shi and colleague added the ApoE4 gene, or removed ApoE entirely. In line with previous studies, addition of the ApoE4 gene to P301S mice accelerated the disease process in these animals, which showed much higher levels of brain atrophy than P301S mice that lacked ApoE entirely. Interestingly, when P301S/ApoE4 mice were treated with a drug that ablated microglia they were almost fully protected against neurodegeneration. When the researchers looked more closely at the brains of these animals, they observed that the microglia within were abundant, but not activated. They also noted that the extent of microglial activation was correlated with the quantity of phosphorylated, pathological tau proteins in the brains of AD mice. This suggests that the activation status of microglia, but not their absolute number, determines their impact on neurodegeneration. Together, these results indicate that the disease-accelerating effect of ApoE4 in tauopathy models is largely due to its regulation of microglial activation.
http://jem.rupress.org/content/early/2019/10/09/jem.20190980/
