▎ WuXi AppTec content team editor
Alzheimer's disease (AD) is becoming one of the most burdened diseases in the world. In response to this disease, many researchers and clinicians are working on blood tests, genetic analysis, big data and other ways to develop ways to detect and diagnose Alzheimer's disease early.
Recently, a research paper by Professor Chen Xu and Professor Zhong Sheng of the University of California, San Diego (UCSD) as co-corresponding authors was published in the latest issue of the academic journal Cell Metabolism, which provides a potential biomarker for the early screening and diagnosis of late-onset Alzheimer's disease through the verification of two mouse models and four populations.
In a previous work published in 2020, Professor Zhong and collaborators observed in multiple cohorts of AD patients that a gene encoding phosphoglycerate dehydrogenase (PHGDH) showed a continuous increase in protein and mRNA expression in relevant brain regions. Although this change occurs inside the brain, it can be assessed by liquid biopsy because there is a consistent increase in free RNA (exRNA) of the PHGDH gene in plasma.
On this basis, Zhongsheng Laboratory, in collaboration with the UC San Diego Chen Xu Laboratory, UC Irvine Professor Xu Xiangmin, and Professor Tan Zhiqun, further examined the relationship between changes in PHGDH and the development of Alzheimer's disease through more different cohorts and animal experiments, and also proposed an explanation for why this signal can be used to predict the onset of AD.
▲ Related reading: "One drop of blood" predicts Alzheimer's disease, 15 years of clinical tracking UCSD bell team brings a breakthrough in liquid biopsy (Image source: 123RF)
PHGDH is an enzyme that cells need to synthesize L-type serine, which helps regulate synapse function by binding to specific receptors at neuronal junctions, i.e., synapses. Some animal experiments and clinical studies have provided evidence that when a gene encoding PHGDH is mutated or missing, brain development is affected due to a serine deficiency.
During the development of Alzheimer's disease, the change in PHGDH levels seems to be the opposite: it continues to increase as the course progresses.
Image credit: 123RF
To confirm this phenomenon, the researchers used two transgenic mouse models that mimic human AD pathology to detect levels of the PHGDH protein and mRNA in the brain. The results of multiple laboratory replicates showed that with the increase in pathological proteins closely related to AD (amyloid Aβ and pathological tau protein), phGDH expression in the hippocampus, an important brain region responsible for learning and memory, increased significantly, and the difference with the control group of mice began to appear from before the pathology was developed.
Animal experiments have also shown that astrocytes are a major cell type with increased expression of the PHGDH protein. Astrocyte cells provide nutrients to the nerves, including L-type serine.
This result is supported by more clinical cohort data. By analyzing mononuclear transcriptome data from multiple cohorts again, the researchers observed a continuous increase in astrocyte PHGDH expression levels, both as the pathology of AD went from scratch to nothing or as symptoms worsened. Analysis of mass spectrometry datasets yielded similar results.
The researchers note that these new analysis results are consistent with previous studies that hippocampus PHGDH expression increases as patients' overall cognitive function declines.
▲Data analysis of multiple clinical populations showed that with the development of AD pathology and symptoms, PHGDH expression increased (Image source: References[1])
The researchers further extrapolated the underlying mechanism by which PHGDH continues to increase expression and develop aD. They propose that increased PHGDH expression in astrocytes, raising the basal level of synaptic activity through L-type serine, leads to overexcitation of neurons, which continue to induce an increase in astrocytes, forming a vicious cycle.
"If this hypothesis is correct, inhibiting the expression of PHGDH in astrocytes may alleviate excitatory toxicity." The paper states.
Notably, this result raises a warning for a potential current strategy for the treatment of AD, namely oral L-type serine through dietary supplementation. The researchers note that considering long-term serine supplementation may lead to neuronal excitatory toxicity, "the idea of 'using oral L-serine (L-serine) for the treatment of AD' needs to be treated with caution." ”
Professor Chen Xu concluded: "This article refutes the recent heat transfer of 'the therapeutic effect of oral L-type serine on Alzheimer's disease through clinical data from two mouse models and four populations, and also supports the ability of PHGDH's free RNA to detect spontaneous Alzheimer's disease in the blood test." ”
Resources:
[1] Xu Chen et al., (2022) PHGDH expression increases with progression of Alzheimer’s disease pathology and symptoms. Cell Metabolism.Doi: https://doi.org/10.1016/j.cmet.2022.02.008
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