On 10 July, Dr Ana Griciuc and colleagues at Massachusetts General Hospital in Boston published their new research findings in Neuron, showing that TREM2 acts downstream of CD33 during the development of neuroinflammation in animal models of Alzheimer’s disease (AD).
Recent research has highlighted a prominent role for neuroinflammation (inflammation that is localised to the brain) during the development of AD. Neuroinflammation is primarily controlled by microglia, brain immune cells that adopt different – and opposing - behaviours once activated during disease development. ‘M2’ variant microglia can dampen AD-associated neuroinflammation by chewing up amyloid plaques; conversely, ‘M1’ variant microglia promote neuroinflammation, releasing factors that damage neurons and increase amyloid deposition.
TREM2 and CD33 are thought to regulate microglial decision-making, pushing microglia towards ‘protective’ M2 or ‘inflammatory’ M1 fates, respectively. However, it is not yet clear whether these two proteins have interacting effects: whether targeting pathological CD33 will affect the beneficial actions of TREM2, or vice versa. Dr Griciuc and colleagues therefore set out to evaluate TREM2 and CD33 in AD-associated neuroinflammation, using mouse models of AD in which the TREM2 and CD33 genes were knocked out individually or in combination.
Using this preclinical approach, the researchers showed that the cognitive benefits of removing CD33 in AD mice were undone when TREM2 was also knocked out. Similarly, the reduction in amyloid plaque load in AD mice lacking CD33 was reversed when TREM2 was also removed. Gene expression analysis of microglia from these mice pointed to a few culprit pathways, including inflammatory regulators such as interleukin 1β. Together, these results allowed the researchers to situate TREM2 ‘downstream’ of CD33, suggesting that therapeutic strategies targeting CD33 will only be beneficial if TREM2 is present.
https://www.cell.com/neuron/pdfExtended/S0896-6273(19)30560-4