Blood test for Alzheimer's disease?

▎WuXi PharmaTech Content Team Editor Alzheimer's disease (AD) is becoming one of the most burdened diseases in the world
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In response to this disease, many researchers and clinicians are working on developing methods for early detection and diagnosis of Alzheimer's disease through blood tests, genetic analysis, and big data
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A few days ago, a research paper by Professor Xu Chen and Professor Zhong Sheng from the University of California, San Diego (UCSD) as co-corresponding authors was published in the latest issue of the academic journal Cell Metabolism.
Through two mouse models and four human populations Validation to provide a potential biomarker for early screening and diagnosis of late-onset Alzheimer's disease
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In a work previously published in 2020, Professor Zhong Sheng and collaborators observed in multiple cohorts of AD patients that a gene encoding phosphoglycerate dehydrogenase (PHGDH) had protein and The phenomenon of continuous increase in mRNA expression
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This change, although occurring inside the brain, can be assessed by liquid biopsy because there is also a consistent increase in free RNA (exRNA) of the PHGDH gene in plasma
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On this basis, Zhongsheng Laboratory cooperated with Chen Xu’s laboratory at the University of California, San Diego, Professor Xu Xiangmin and Professor Tan Zhiqun at the University of California, Irvine, and further tested the changes in PHGDH and Alzheimer’s through more different cohorts and animal experiments.
The relationship between the progression of Haimer's disease also provides an explanation for why this signal can be used to predict the onset of AD
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▲Related reading: "A drop of blood" predicts Alzheimer's disease, 15 years of clinical follow-up UCSD Zhongsheng team brought a breakthrough in liquid biopsy (Image source: 123RF) PHGDH is an enzyme required for cells to synthesize L-type serine, and serine binds nerve cells Specific receptors at meta-junctions, or synapses, help regulate synapse function
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Several animal experiments and clinical studies have provided evidence that when the gene encoding PHGDH is mutated or deleted, brain development is affected due to serine defects
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In the development of Alzheimer's disease, the changes in PHGDH levels appear to be reversed: they continue to increase as the disease progresses
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Image credit: 123RF To confirm this phenomenon, the researchers examined the levels of PHGDH protein and mRNA in the brain using two transgenic mouse models that mimic human AD pathology
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Repeated results from multiple laboratories showed that with the increase of pathological proteins closely related to AD (amyloid Aβ and pathological tau protein), the expression of PHGDH was significantly increased in the hippocampus, an important brain region responsible for learning and memory.
, and the differences from the control mice began to appear before they developed pathology
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Animal experiments also showed that astrocytes were a major cell type with increased PHGDH protein expression
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Astrocyte cells supply nerves with nutrients, including L-serine
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This result is supported by additional clinical cohort data
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By reanalysing mononuclear transcriptome data from multiple cohorts, the researchers observed a continuous increase in astrocyte PHGDH expression levels, either as AD pathology progressed from inception or as symptoms worsened
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Analysis of mass spectrometry datasets yielded similar results
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The researchers noted that the results of these new analyses are consistent with previous studies showing that PHGDH expression in the hippocampus increased as patients' overall cognitive function declined
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▲Data analysis of multiple clinical populations showed that with the development of AD pathology and symptoms, the expression of PHGDH increased (Image source: Reference [1]) The researchers further inferred the potential mechanism of the continuous increase in the expression of PHGDH and the development of AD
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They propose that increased PHGDH expression in astrocytes raises the basal level of synaptic activity via L-type serine, leading to neuronal hyperexcitability, which continues to induce astrocytes to increase, forming a vicious circle
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"If this hypothesis is correct, inhibition of PHGDH expression in astrocytes can alleviate excitotoxicity,
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the paper states
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Notably, this result raises a caveat for a current potential strategy for AD treatment, namely oral L-serine via dietary supplements
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The researchers pointed out that considering long-term serine supplementation may lead to neuronal excitotoxicity, "the idea of ​​'the use of oral L-serine (L-serine) for the treatment of AD' needs to be treated with caution
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" Professor Chen Xu concluded: "This article The clinical data of two mouse models and four populations refuted the recently popular 'the therapeutic effect of oral L-serine on Alzheimer's', and also confirmed the ability of PHGDH-free RNA to detect spontaneous Alzheimer's disease early in blood tests
"
Reference: [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.
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