International Business Department           Liu Bojia           July 22, 2024

  Diseases that affect the cognitive function of the brain, such as Alzheimer's disease and Parkinson's disease, are highly prevalent among the elderly. After years of research, scientists have discovered that the misbehaviour of one type of cell in the brain may be behind the cause or exacerbation of these neurodegenerative diseases: microglial cells.

  Microglia are immune cells that reside in the central nervous system and perform a number of functions in the brain, including guiding brain development, engulfing diseased or damaged cells, and pruning synapses, the special structures between nerve cells that transmit signals, among others.

  But in a recent study published in Cell, scientists have discovered a new way in which microglia affect neuronal function that is closely linked to aging and may play a role in the cognitive changes and neurodegenerative diseases that occur with age.

  One of the paper's co-corresponding authors, Professor Beth Stevens, currently at Harvard Medical School and Boston Children's Hospital, has worked for many years on C1q, a complement protein secreted by microglia, and has found that C1q affects neuronal synapses. Particularly during early brain development, C1q appears alongside other complement proteins at neuronal synapses, acting as a surface ‘marker’ that allows microglia to engulf the labelled synapses or neurons, thus deleting unwanted synapses and ensuring that nerve signals are transmitted more efficiently.

  And in this newly published paper, the team accidentally discovered in the brains of senescent animals that C1q also works inside neurons, and that this function seems to be absent from other complement proteins.

  In the paper, the authors describe that when examining mice of different ages, they noticed a dramatic increase in brain C1q protein levels as the animals aged, and unexpectedly found the signal to be inside neurons in high concentrations.

  These phenomena piqued the scientists' curiosity: how does the C1q secreted by microglia enter neurons during ageing? What is it doing there?

  Subsequent studies have solved the mystery one by one. The researchers found that the C1q secreted by microglia is ‘eaten’ by neurons. Through the so-called ‘endocytosis’, neurons can take up extracellular C1q protein; and the special structure of C1q protein, especially the collagen-like structural domain, is very crucial for neurons to take up C1q protein.

  Further analyses also showed that C1q binds to the ribonucleoprotein (RNP) complex in the cytoplasm of neurons. Ribonucleoprotein is a complex composed of RNA and protein. And in vitro experiments revealed that the interaction of C1q with the RNP complex cannot be separated from the RNA molecules inside the nerve cells.

  From this pattern of interaction, the researchers surmised that C1q interferes with the process of protein translation in neuronal cells, and the experimental results verified this speculation. When the researchers removed C1q from adult mice by gene knockout, they found that their neurons produced significantly more proteins and the protein balance within the brain changed. Moreover, this effect was strongly related to age, with middle-aged mice experiencing more pronounced protein changes due to the lack of C1q than younger mice.

  At the same time, when C1q was deleted from microglia, adult mice also experienced changes in their memory capacity: behavioural tests showed that these mice remembered a newly acquired fearful experience for longer. In other words, neurons that had ingested the protein secreted by microglia affected the animals' learning and memory.

  Taking these results together, the study authors came up with an intriguing conclusion: immune proteins produced by microglia affect key protein translation functions inside neuronal cells.

  Considering that C1q levels rise with aging and have also been found to be higher in the brains of Alzheimer's disease patients, the fact that C1q affects key functions within neuronal cells will perhaps be an important breakthrough in slowing down brain aging, or even reversing brain decline, to be discovered in subsequent studies.