Improves in phosphoglycerate dehydrogenase (PHGDH) expression have been demonstrated to add to the progression of Alzheimer disorder (Advertisement)–associated indicators and pathology, in accordance to review findings revealed in the journal Cell Metabolic rate.1
PHGDH is an enzyme necessary for the synthesis of serine, which is a modulator of synaptic plasticity. In point, human mutations in PHGDH can final result in irregular brain development due to serine deficiency, whereas conditional knockout of PHGDH in the mouse hippocampus impairs spatial memory and synaptic plasticity. Primarily based on the regarded value of synaptic pathophysiology to Advertisement, these results elevate the risk that abnormalities in PHGDH expression could be a contributory variable to the pathogenesis of Advert.
The scientists of the present review report that “PHGDH mRNA and protein amounts are amplified in the brains of 2 mouse styles of Advert and/or tauopathy, and are also progressively increased in human brains with no, early, and late Ad pathology, as well as in folks with no, asymptomatic, and symptomatic Advert.” They shown an boost in PHGDH expression in triple transgenic (3xTg-Advert) mice — a model of Advert that develops both of those amyloid-β and tau pathology.
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Originally, the researchers reanalyzed an RNA expression dataset of 3xTg-Ad mice. They observed that at 3 months, when Advertisement pathology has not yet formulated, hippocampal PHGDH mRNA level in 3xTg-Advert mice did not vary appreciably (Bonferroni-corrected P =.682, t examination) from that in nontransgenic (non-Tg) controls. At 12 months, nevertheless, hippocampal PHGDH mRNA stage was substantially larger in 3xTg-Advertisement mice than in non-Tg controls (Bonferroni-corrected P =.015, t take a look at).
Next, the researchers done an immunofluorescent confocal analysis, in get to confirm the 2020 findings from Le Douce and colleagues.2 To make certain reproducibility, they attained hippocampal sections from 5 pairs of 6-thirty day period-old woman 3xTg-Advertisement mice and non-Tg controls. These conclusions confirmed that hippocampal PHGDH immunostaining was enhanced significantly in 3xTg-Ad mice compared with non-Tg mice (P =.0039 n=5/group, permutation exam). Since the 5 pairs of mice ended up elevated in 4 various laboratories, thus arguing strongly against the presence of laboratory-to-laboratory variation. Additional, an enhance in glial fibrillary acidic protein (GFAP) expression was observed in 3xTg-Advert mice as opposed with non-Tg mice.
Also, an maximize in PHGDH expression was detected in human P301S tau transgenic mice (PS19). Acknowledging that “no single mouse model can fully recapitulate human Advertisement,” the researchers questioned no matter if their observation in 3xTg-Ad mice could be replicated in PS19 mice — a model of tauopathy that is impartial of amyloid-β. They evaluated improvements in PHGDH protein levels with the use of immunohistochemistry and Western blots. Hippocampal PHGDH exhibited considerable colocalization with GFAP in PS19 mice, therefore substantiating the astrocyte expression of PHGDH.
PHGDH protein degrees were improved in the hippocampus of 1-thirty day period-previous PS19 mice compared with non-Tg littermate controls (Western blot P <.0001 unpaired t-test, n=8 for PS19 mice and n=7 for non-Tg mice), thus indicating that expression of a human mutant tau transgene is sufficient to induce hippocampal PHGDH expression.
Sequential increase in PHGDH mRNA expression with concomitant AD pathology has been reported in humans. The researchers reanalyzed a total of 80,660 single-nucleus transcriptomes from 24, 15, and 9 individuals with no AD, early AD, and late AD pathology, respectively. Consistent with astrocyte expression of PHGDH that was reported, PHGDH was detected in approximately 10% to 25% of astrocytes, oligodendrocytes, and oligodendrocyte precursor cells, as well as in <4% of excitatory and inhibitor neurons, endothelial cells, and microglia.
PHGDH exhibits a sequential increase in expression from no pathology, to early pathology, and to late pathology in astrocytes (P =.016). The fraction of PHGDH-expressing astrocytes does not increase from no pathology to early pathology, implying that the early pathology-associated PHGDH expression increase is due to an increase in the expression level per cell, rather than to an increase in the proportion of PHGDH-expressing cells.
The reproducible rise in PHGDH expression during both pathologic and symptomatic developments of AD suggests “different underlying mechanisms between PHGDH deficiency and AD.”
The results of the current analysis support the prior observation of an AD-associated increase in PHGDH extracellular RNA (exRNA) in human plasma. The findings also help to clarify why the longitudinal increase in PHGDH exRNA can predict the clinical diagnosis of AD. Taken together, “these data nominate circulating PHGDH exRNA as a possible diagnostic biomarker of late-onset AD.”
Disclosure: One of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the author’s disclosures.
1. Chen X, Calandrelli R, Girardini J, et al. PHGDH expression increases with progression of Alzheimer’s disease pathology and symptoms. Cell Metab. Published online May 3, 2022. doi:10.1016/j.cmet.2022.02.008
2. Le Douce J, Maugard M, Veran J, et al. Impairment of glycolysis-derived L-serine production in astrocytes contributes to cognitive deficits in Alzheimer’s disease. Cell Metab. Published online March 3, 2020. doi:10.1016/j.cmet.2020.02.004