Elevated PHGDH May Act As Blood Biomarker for Early Alzheimer Disease

Increases in phosphoglycerate dehydrogenase (PHGDH) expression have been shown to contribute to the progression of Alzheimer disease (AD)–associated symptoms and pathology, according to study findings published in the journal Cell Metabolism.¹

PHGDH is an enzyme required for the synthesis of serine, which is a modulator of synaptic plasticity. In fact, human mutations in PHGDH can result in abnormal brain development due to serine deficiency, whereas conditional knockout of PHGDH in the mouse hippocampus impairs spatial memory and synaptic plasticity. Based on the known importance of synaptic pathophysiology to AD, these findings raise the possibility that abnormalities in PHGDH expression might be a contributory factor to the pathogenesis of AD.

The researchers of the current study report that “PHGDH mRNA and protein levels are increased in the brains of 2 mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD.” They demonstrated an increase in PHGDH expression in triple transgenic (3xTg-AD) mice — a model of AD that develops both amyloid-β and tau pathology.

Initially, the researchers reanalyzed an RNA expression dataset of 3xTg-AD mice. They observed that at 3 months, when AD pathology has not yet developed, hippocampal PHGDH mRNA level in 3xTg-AD mice did not differ significantly (Bonferroni-corrected P =.682, t test) from that in nontransgenic (non-Tg) controls. At 12 months, however, hippocampal PHGDH mRNA level was significantly higher in 3xTg-AD mice than in non-Tg controls (Bonferroni-corrected P =.015, t test).

Next, the researchers performed an immunofluorescent confocal analysis, in order to confirm the 2020 findings from Le Douce and colleagues.² To ensure reproducibility, they obtained hippocampal sections from 5 pairs of 6-month-old female 3xTg-AD mice and non-Tg controls. These findings showed that hippocampal PHGDH immunostaining was increased significantly in 3xTg-AD mice compared with non-Tg mice (P =.0039; n=5/group, permutation test). Since the 5 pairs of mice were raised in 4 different laboratories, thus arguing strongly against the presence of laboratory-to-laboratory variation. Further, an increase in glial fibrillary acidic protein (GFAP) expression was observed in 3xTg-AD mice compared with non-Tg mice.

Additionally, an increase in PHGDH expression was detected in human P301S tau transgenic mice (PS19). Realizing that “no single mouse model can fully recapitulate human AD,” the researchers questioned whether their observation in 3xTg-AD mice could be replicated in PS19 mice — a model of tauopathy that is independent of amyloid-β. They evaluated changes in PHGDH protein levels with the use of immunohistochemistry and Western blots. Hippocampal PHGDH exhibited significant colocalization with GFAP in PS19 mice, thus substantiating the astrocyte expression of PHGDH.

PHGDH protein levels were increased in the hippocampus of 1-month-old 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. 

Reference 

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