Polyglutamine binding protein 1(PQBP1) mediates high calorie-induced cognitive impairment

In today's high-stress society, overeating and obesity have become major issues. A high-calorie state leads to an excess of insulin in the body; over time, this results in reduced tissue responsiveness to insulin and impaired insulin secretion, eventually progressing to diabetes. It has become evident that this process not only leads to a decline in brain function but also increases the risk of Alzheimer's disease. Furthermore, while it is believed that a high-calorie state impairs cognitive function even before the onset of Alzheimer's disease, the underlying mechanism had remained unclear.

 Meanwhile, the PQBP1 gene was originally identified by our research group led by Professor Okazawa (then at the Department of Neurology, The University of Tokyo) as a molecule involved in the pathology of neurodegenerative diseases [References 1, 2]. Subsequent large-scale studies in Europe revealed it to be a causative gene for several hereditary intellectual disabilities, including Renpenning syndrome [Reference 3]. PQBP1 is a factor that regulates "RNA splicing," the process by which pre-mRNA matures into mRNA. It has been shown that synapse-related molecules in neurons and cell-cycle molecules in neural stem cells serve as targets for PQBP1-dependent RNA splicing [References 4, 5, 6].

 Moreover, it has been demonstrated that PQBP1 levels in neurons decrease in patients with Alzheimer's disease, leading to synaptic abnormalities [Reference 7]. Additionally, in microglia—cells responsible for innate immunity in the brain—PQBP1 has been found to recognize Tau protein and induce neuroinflammation associated with Alzheimer's disease and other Tau-related neurodegenerative disorders [Reference 8].

This study just published in Molecular Psychiatry on September 12th 2026(Huang et al, 2026) began with the discovery that sustained high-calorie conditions—whether short-term or long-term—lead to reduced transcription levels of PQBP1, a factor associated with cognitive function, within brain tissue. This reduction was observed specifically in neurons, not in astrocytes or microglia. The study revealed that the resulting decrease in PQBP1 protein inhibits its primary function—the RNA splicing of synapse-related molecules—thereby causing abnormalities in synapse-related proteins and ultimately leading to a reduction in synapse numbers and functional impairment.

It was also found that PQBP1 transcription is regulated by PPARγ, a transcription factor known to play a crucial role in various biological processes, including diabetes. Furthermore, the study demonstrated that high-calorie conditions activate insulin signaling pathways that phosphorylate PPARγ and inhibit its transcriptional activity, thereby reducing PQBP1 transcription levels (Figure 1).

Additionally, the research group used RNA-seq analysis to identify the specific synapse-related molecules most affected by the changes in RNA splicing caused by the reduction of PQBP1 protein. They then administered treatments to mice exhibiting cognitive decline due to a high-calorie diet; these treatments included an oral diabetes drug that enhances PPARγ function, gene therapy targeting PQBP1, and gene therapy targeting the specific synapse-related molecules regulated by PQBP1. Experiments using these animal models demonstrated that these therapeutic approaches alleviated synaptic impairment and cognitive decline in the mice fed a high-calorie diet (Figure 2).

References

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