Rare gene variants offer new insights into Alzheimer's disease biology

The role of PLCG2 – a gene linked to Alzheimer's disease – in brain health may be broader than previously thought, a new study suggests.

Both environmental and genetic factors can increase the likelihood of an individual developing Alzheimer's disease, a common neurodegenerative condition associated with a loss of neurons and a weakening of their connections (synapses). The PLCG2 gene has emerged as an important modifier of Alzheimer's disease risk, specifically a rare protective variant that increases expression. Researchers at the University of Eastern Finland and the INSERM research institute in Paris, France, have now identified other rare PLCG2 variants linked to a tenfold increase in the chance of being diagnosed with the condition.

'Because the proportion of risk attributable to genetic susceptibility factors for [Alzheimer's disease] has been estimated to be between 60 percent and 80 percent in twin studies, defining the [Alzheimer's disease] genetic component should help in better understanding the pathophysiological processes and in generating complementary or alternative hypotheses,' wrote the authors in their paper published in Nature Genetics.

The team used a high-content assay to assess the impact of 198 genes linked to Alzheimer's disease on synapses in rat primary neuronal cultures. Nine genes, including Plcg2, were shown to strongly modulate synaptic density. Further experiments revealed that reducing the expression of Plcg2 in mouse neurons from a brain region associated with memory consistently disrupted the branching patterns these cells form to connect with each other, as well as their synapses. This resulted in synaptic dysfunction – one of the earliest pathological changes to occur in Alzheimer's disease.

PLCG2 silencing also impaired synaptic function in human stem cell-derived neurons. This led to an increase in amyloid-β levels and phosphorylation of tau – proteins which become misfolded in Alzheimer's disease, preventing neurons from communicating effectively. The researchers then examined how reduced PLCG2 expression altered gene activity patterns in individual neurons, showing that many pathways involved in synaptic and neuronal functions became dysregulated.

Finally, the team sought another source of evidence for the impact of reduced PLCG2 activity on Alzheimer's disease. Combing through European human genetic databases, they revealed that individuals carrying rare loss-of-function PLCG2 variants had a tenfold increase in developing the condition.

These results represent a departure from how PLCG2 had been understood so far. While its potential role in Alzheimer's disease had already been identified, it had mostly been studied not in neurons, but in microglia, the brain's resident immune cell population. The findings indicate that its influence on the development of Alzheimer's disease may go beyond its role in immune activity, with a direct impact on neuronal processes as well.

Overall, this work strengthens the potential for PLCG2 to be a promising therapeutic target for Alzheimer’s disease and similar conditions, opening new avenues for treatment or prevention.