Mechanism Revealed: PLCG2 Deficiency within Neurons Induces Synaptic Collapse and Accumulation of Alzheimer's Disease Pathological Proteins
Background
Alzheimer's disease (AD) research has long focused on microglia, the brain's immune cells. The prevailing view has been that dysfunction in microglia, which clear waste products in the brain, triggers cognitive decline. In particular, the Phospholipase C-gamma 2 (PLCG2) gene has been classified as a key factor that regulates immune responses and is primarily expressed in microglia. Despite its strong genetic association, the specific role of PLCG2 in neurons themselves has remained unclear.
Previous studies have focused on the microglia-centric immune mechanisms, failing to elucidate the direct impact on neurons and synaptic function. Given that the core pathology of Alzheimer's disease, including amyloid-beta (Aβ) accumulation and Tau hyperphosphorylation, begins within neurons, this is a critical issue to address. To this end, Dr. Audrey Coulomb and her team at the Pasteur Institute in Lille, France, focused on the impact of PLCG2 within neurons on the brain's cellular network.
Key Findings
The research team aimed to analyze the function of PLCG2 using primary neuronal cultures from mice and human induced pluripotent stem cell (iPSC)-derived neuronal cultures (hNCs). They designed a strategy to inhibit PLCG2 expression in dentate gyrus neurons of mice using short hairpin RNA (shRNA). As a result, they observed a sharp decrease in the density of dendritic spines, which are dendritic protrusions, and a disruption of their morphology. This phenomenon indicates that synapses, the structural pathways for neuronal communication, are structurally destroyed.
These structural changes were directly linked to severe functional impairments and pathological phenomena. Neurons with suppressed PLCG2 expression showed significantly reduced synaptic transmission efficiency, and the accumulation of Aβ protein, a hallmark of Alzheimer's disease, was noticeably increased. In particular, the proportion of highly toxic amyloid-beta 42 (Aβ42) increased, and abnormal phosphorylation of Tau protein, which destroys neurons, was also observed.
The research team conducted additional experiments using a human neuronal cell model, targeting the R953* loss-of-function (LoF) mutation, a rare genetic variant found in actual patients. Neurons carrying this mutation showed a significant decrease in PLCG2 expression compared to normal cells. This gene deficiency abnormally stimulated the AKT/GSK3β signaling pathway, leading to Tau protein hyperphosphorylation and disrupting the expression of Neurexin, a synaptic adhesion protein. Surprisingly, when normal PLCG2 genes were reintroduced into neurons with suppressed expression, the damaged synaptic function was restored, and the levels of pathological proteins returned to normal.
Significance and Prospects
This study calls for a paradigm shift in the way we view the causes of Alzheimer's disease. Until now, the PLCG2 gene has been primarily interpreted as a regulator of immune responses related to microglia. However, this analysis has revealed that it has an independent role within neurons to directly protect synapses and prevent the accumulation of pathological substances. With the identification of distinct roles of PLCG2 in immune cells and neurons, the development of therapeutic strategies is entering a new phase.
However, there are still many challenges to be solved before the results of this study can be applied to the development of therapeutics. The results presented by the research team were obtained in controlled environments, such as cell culture dishes and mouse models; therefore, follow-up studies are needed to verify whether the same effects occur in the complex human brain environment. A precise drug delivery technology that selectively increases PLCG2 activity in neurons is also a critical requirement. Nevertheless, this discovery is expected to be an important milestone in the quest to overcome Alzheimer's disease by identifying a therapeutic target that prevents synaptic damage.
Nature Genetics, Published online: 14 August 2026; doi:10.1038/s41588-026-02709-5This study demonstrates that downregulation of PLCG2, primarily in neurons, impairs synaptic function and elevates amyloid-β levels and Tau protein phosphorylation.
The most immediate application scenario is genetic screening of Alzheimer's disease patients. If the PLCG2 R953* mutation is identified in a patient's genome, it may be possible to classify them as being at risk of synaptic collapse and to initiate targeted management from the beginning. In terms of treatment, a strategy is envisioned to deliver gene therapy to induce normal PLCG2 expression in the patient's brain neurons, thereby preserving synaptic density. This is expected to overcome the limitations of existing antibody therapies that simply remove Aβ or Tau proteins and to provide a fundamental treatment alternative that preserves the brain's cellular network and prevents cognitive decline. Pharmaceutical companies are also expected to accelerate the discovery of new candidate substances by adding a new pathway of direct neuronal activation to their existing pipelines targeting microglia.