Why do some people develop Alzheimer’s disease while others remain mentally sharp into old age? Part of the answer may lie in a gene that appears to influence how well brain cells maintain their connections and protect themselves from damage.
The gene is called PLCG2. Scientists already knew that certain versions of it can change a person’s risk of Alzheimer’s, but a new study reveals that its role in the brain may be much broader than previously thought.
The international research was led by the University of Eastern Finland and France’s INSERM research institute. The findings were published in the scientific journal Nature Genetics.
Alzheimer’s is a progressive brain disease and the leading cause of dementia. It usually begins with mild memory difficulties but can eventually affect language, judgment, personality and the ability to perform basic daily tasks.
Inside the brain, Alzheimer’s is associated with the loss of connections between nerve cells and, eventually, the death of those cells. Abnormal forms of two proteins, beta-amyloid and tau, are also strongly linked with the disease.
Genes can influence this process, although most cases are not caused by a single inherited mutation. Instead, many genetic differences can slightly increase or decrease risk, while a smaller number of rare variants can have much stronger effects.
PLCG2 has become especially interesting because one rare version, known as P522R, appears to protect against Alzheimer’s. This version increases the activity of the PLCγ2 enzyme made by the gene.
That observation gave researchers an important clue. If greater PLCγ2 activity is protective, perhaps unusually low activity has the opposite effect and leaves the brain more vulnerable to Alzheimer’s.
The new study tested this idea using two very different sources of evidence. Scientists first examined genetic information from European populations and then carried out experiments on human nerve cells produced from stem cells.
The genetic analysis identified rare PLCG2 variants that interfere with the gene’s normal function. Carriers of these variants had about a 10-fold higher risk of Alzheimer’s disease than people without them.
This sounds dramatic, but it needs careful interpretation. The variants are uncommon, and relative risk is not the same as certainty, so carrying one does not mean a person is destined to develop dementia.
The laboratory experiments helped explain why these variants might matter. When researchers studied an Alzheimer’s-associated form of PLCG2, neurons produced less of the PLCγ2 protein and showed more disease-related changes.
The scientists also reduced PLCG2 activity directly in human neurons. The cells then developed abnormal changes in their dendrites, the branch-like structures that receive signals from neighboring nerve cells.
The neurons also had weaker synapses. A synapse is the tiny meeting point where one nerve cell passes a message to another, and trillions of these connections allow the brain to store memories, process information and control behavior.
Synapse loss is one of the changes most closely linked with declining thinking ability in Alzheimer’s disease. Finding that reduced PLCG2 activity can weaken these connections therefore gives researchers a possible explanation for how the gene influences disease risk.
Lower PLCG2 function also increased Alzheimer’s-related changes involving beta-amyloid and tau. These proteins normally exist in the body, but abnormal forms can build up in the brain and are central features of Alzheimer’s disease.
The researchers went even deeper by examining patterns of gene activity in individual cell nuclei. They found that lowering PLCG2 affected networks of genes needed for healthy communication, connections and signaling between neurons.
This result challenges an older assumption about PLCG2. Scientists had mainly studied the gene in microglia, the brain’s resident immune cells, because PLCγ2 plays an important role in immune signaling.
The new work suggests neurons themselves also depend on PLCG2. That means the gene may influence Alzheimer’s through more than one type of brain cell and through several biological processes at the same time.
From a treatment perspective, this is potentially exciting. If reduced PLCγ2 activity contributes to disease while increased activity is protective, a medicine designed to safely boost this pathway might one day help prevent or slow Alzheimer’s.
But there is a major gap between identifying a promising biological target and creating an effective drug. Scientists first need to determine how much PLCγ2 activity is beneficial, which brain cells should be targeted and whether increasing the enzyme could cause unwanted effects elsewhere in the body.
The stem-cell experiments are another limitation. Laboratory-grown neurons are useful for studying individual mechanisms, but they do not fully reproduce an older human brain containing many cell types, blood vessels, immune responses and decades of accumulated changes.
The genetic findings are compelling because naturally occurring human variants point toward the same biological pathway. Still, additional research in larger populations and animal models, followed eventually by human trials of any potential treatment, will be necessary.
The study therefore does not offer a new Alzheimer’s medicine today. Its value is more fundamental: it provides a stronger explanation for why PLCG2 changes disease risk and identifies neuronal PLCγ2 activity as a possible protective system that researchers may be able to use in the future.
If these findings are confirmed, PLCG2 could become an important piece of the Alzheimer’s puzzle. The research also shows how studying rare people with protective or harmful gene variants can reveal biological pathways that may eventually lead to treatments for everyone.
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Source: University of Eastern Finland.
