Alzheimer’s disease: PHGDH exRNA levels increase up to two years earlier


Researchers at the University of California San Diego discovered that high blood levels of RNA produced by the PHGDH gene could serve as a biomarker for early detection of Alzheimer’s disease.

The work could lead to the development of a blood test to identify individuals who will develop the disease years before they show symptoms.

The team published their findings in Current Biology.

The PHGDH gene produces RNA and proteins that are critical for brain development and function in infants, children and adolescents. As people get older, the gene typically ramps down its production of these RNAs and proteins.

The new study, led by Sheng Zhong, a professor of bioengineering at the UC San Diego Jacobs School of Engineering in collaboration with Dr. Edward Koo, a professor of neuroscience at the UC San Diego School of Medicine, suggests that overproduction of a type of RNA, called extracellular RNA (exRNA), by the PHGDH gene in the elderly could provide an early warning sign of Alzheimer’s disease.

“Several known changes associated with Alzheimer’s disease usually show up around the time of clinical diagnosis, which is a little too late. We had a hunch that there is a molecular predictor that would show up years before, and that’s what motivated this study,” Zhong said.

The discovery was made possible thanks to a technique developed by Zhong and colleagues that is sensitive enough to sequence tens of thousands of exRNAs in less than one drop of blood.

The method, dubbed SILVER-SEQ, was used to analyze the exRNA profiles in blood samples of 35 elderly individuals 70 years and older who were monitored up to 15 years prior to death.

The subjects consisted of 15 patients with Alzheimer’s disease; 11 “converters,” which are subjects who were initially healthy then later developed Alzheimer’s; and 9 healthy controls. Clinical diagnoses were confirmed by analysis of post-mortem brain tissue.

The results showed a steep increase in PHGDH exRNA production in all converters approximately two years before they were clinically diagnosed with Alzheimer’s.

PHGDH exRNA levels were on average higher in Alzheimer’s patients.

They did not exhibit an increasing trend in the controls, except for in one control that became classified as a converter.

The researchers note some uncertainty regarding the anomalous converter. Since the subject died sometime during the 15-year monitoring, it is unclear whether that individual would have indeed developed Alzheimer’s if he or she lived longer, Zhong said.

The team acknowledges additional limitations of the study.

“This is a retrospective study based on clinical follow-ups from the past, not a randomized clinical trial on a larger sample size. So we are not yet calling this a verified blood test for Alzheimer’s disease,” said co-first author Zixu Zhou, a bioengineering alumnus from Zhong’s lab who is now at Genemo Inc., a startup founded by Zhong.

“Nevertheless, our data, which were from clinically collected samples, strongly support the discovery of a biomarker for predicting the development of Alzheimer’s disease.”

The discovery was made possible thanks to a technique developed by Zhong and colleagues that is sensitive enough to sequence tens of thousands of exRNAs in less than one drop of blood.

In addition to randomized trials, future studies will include testing if the PHGDH biomarker can be used to identify patients who will respond to drugs for Alzheimer’s disease.

The team is also open to collaborating with Alzheimer’s research groups that might be interested in testing and validating this biomarker.

“If our results can be replicated by other centers and expanded to more cases, then it suggests that there are biomarkers outside of the brain that are altered before clinical disease onset and that these changes also predict the possible onset or development of Alzheimer’s disease,” Koo said.

“If this PDGDH signal is shown to be accurate, it can be quite informative for diagnosis and even treatment response for Alzheimer’s research.”

This study was performed in collaboration with Genemo Inc.

The extracellular RNAs (exRNAs) from human biofluid have recently been systematically characterized.

However, the correlations of biofluid exRNA levels and human diseases remain largely untested. Here, considering the unmet need for presymptomatic biomarkers of sporadic Alzheimer’s disease (AD), we leveraged the recently developed SILVER-seq (small-input liquid volume extracellular RNA sequencing) technology to generate exRNA profiles from a longitudinal collection of human plasma samples.

These 164 plasma samples were collected from research subjects 70 years or older with up to 15 years of clinical follow-up prior to death and whose clinical diagnoses were confirmed by pathological analysis of their post mortem brains. The exRNAs of AD-activated genes and transposons in the brain exhibited a concordant trend of increase in AD plasma
in comparison with age-matched control plasma.

However, when we required statistical significance with multiple testing adjustments, phosphoglycerate dehydrogenase (PHGDH) was the only gene that exhibited consistent upregulation in AD brain transcriptomes from 3 independent cohorts and an increase
in AD plasma as compared to controls.

We validated PHGDH’s serum exRNA and brain protein expression increases in AD by using 5 additional published cohorts.

Finally, we compared the time-course exRNA trajectories between ‘‘converters’’ and controls. Plasma PHGDH exRNA exhibited presymptomatic increases in each of the 11 converters during their transitions from normal to cognitive impairment but remained stable over the entire follow-up period in 8 out of the 9 control elderly subjects. These data suggest the potential utilities of plasma exRNA levels for screening and longitudinal exRNA changes as a presymptomatic indication of sporadic AD.


The Possibility of Assessing Brain Gene Expression by Blood exRNAs
Despite extracellular RNase activity, circulating exRNAs can be protected by exosomes and extracellular carriers, including lipo- protein complexes and ribonucleoproteins [1, 7]. These protec- tions keep plasma exRNAs at an equilibrium concentration of approximately 10 pmol/L [14]. Clinical utility of plasma exRNA was demonstrated in a special case, in which placentally derived exRNAs were utilized to prenatally detect chromosomal aneuploidy [56]. It had remained an open question as to whether exRNAs may reflect the physiological status of the brain.

Conceptually, brain-derived exRNAs can enter the blood- stream by going through either the lymphatic system or the blood-brain barrier (BBB). The clearance of brain waste by the lymphatic system into the blood circulation has been pro- posed asa means of protection against neurological disorders [57, 58].

Exosomes with their RNA cargos can go across healthy BBB [59]. The BBB leakiness in early AD likely makes it more permissive to the passage of all types of extracellular molecules [60, 61]. Consistent with these concepts, the brain expression level of a brain-specific gene is positively corre- lated with the chances of detecting this gene in plasma (Figure 2), suggesting that circulating exRNAs may be a class of overlooked molecules for assessing the expression of genes within the central nervous system. In this study, we reported a tendency of concordant AD-associ- ated expression changes in brain and plasma in elderlies, thus the possibility of expanding candidate blood bio- markers from Ab and tau proteins and peptides to a wide range of genes that are activated during AD development. This expansion is much needed for research of early indications of AD because the initial molecular changes may well predate the accumulation of toxic Ab and tau species [62].

Figure 2. Association of Brain-Specific Genes and the SILVER-Seq-Detected Genes in Plasma
(A) Histogram of the brain expression levels (the average TPM of GTEx-assayed brain regions) of the brain-specific genes (x axis). These brain- specific genes are categorized into 4 groups of increasing expression levels in brain (vertical shades).
(B) Distributions of the odds ratios between the brain-specific genes in each expression group (TPM = (0,1], (1,10], (10,100], and (100, infinity); x axis) and those genes detected in each plasma sample (SILVER-seq’s TPM > 5). The odds ratio derived from a plasma sample corresponds to a data point in each expression group (vertical shade). Each boxplot summarizes the ratios derived from the control (blue), AD (red), and converter (green) plasma samples.
See also Figure S2 and Table S4.

Limitations of This Study
The APOE genetic statuses are not the same in AD, controls, and converters. Whereas 5 of 15 AD subjects were homozy- gous for ε4, none of the 9 controls and the 11 converters was homozygous for ε4. This difference is consistent with the increased AD risks of the ε4/ε4 genotype. We have controlled for APOE genetic status in all comparison among these research subjects.
This is not a double-blind randomized prospective study and thus cannot control for all possible confounders. The treatments received by the AD patients can be a confounder to the identified differences between AD and controls.

However, this concern is ameliorated by the difference of the longitudinal changes in the prodromal phase of the converts and the longitudinal changes in controls, because the converters did not receive any treatments until the last year or two prior to their full-blown clinical conversion.

SILVER-seq has not been tested as a method for measuring the absolute concentrations of exRNAs. We have therefore devoted all data analyses to the relative changes of normalized SILVER-seq read counts between samples or sample groups. Furthermore, TPM may not be an ideal metric for quantifying ex- RNA levels of coding genes and long non-coding RNA genes, because the exRNAs derived from these genes are often short RNA fragments [11, 14].

Future developments of statistical methods are needed to account for the size distribution and the actual genomic origins of exRNAs as well as possible back-ground noises in SILVER-seq data.

The number of converters whose diagnoses have changed from normal to cognitive impairment is limited. It will be useful for future work to follow additional research subjects over a long period (>10 years) of time and carry out randomized double-blinded an- alyses. We recognize that the challenges of such a future study include the difficulty to find and follow many converters before symptoms due to the lack of power in using genetic variants to predict sporadic AD.

This unique collection of plasma samples from pathology-confirmed participants analyzed in our study is the result of a decades-long effort to longitudinally assess AD and control subjects through the generous support of the National Institute on Aging.

It is difficult to define what is ‘‘absolutely normal’’ in people of age 70 or older because nearly all of them experience some memory or cognitive decline. Indeed, all the control individuals in this study exhibited some pathological changes as expected (Braak stage 1 or 2), although at lower degrees than those in the AD and converter groups (Braak stages 3–6).

Therefore, the ‘‘clean’’ data from people who had both clinical diagnosis and pathological confirmation generated in this study could be particularly useful for explorations of new biomarkers that may or may not be related to the accumulation of Ab or toxic tau in brain [62].

Because the control group all show pathological signs of aging, especially those related to AD-associated changes, albeit to a much lower degree, they are not in this sense absolutely normal.

Given this and heterogeneity between individuals, finding any specific molecular differences between the control and the disease groups may be an exceedingly difficult task. In this context, the observed differentia- tion between the converter groups by PHGDH dynamics as compared to control or AD group is even more noteworthy.

Considering these limitations, we compared our data with the data of other cross-sectional studies. These comparisons re- vealed a consistent trend of AD-associated upregulation of the ERV1 clade of transposons and AMP-AD genes in plasma and in brain. In particular, the AD-associated increase of PHGDH was consistent across 3 cohorts in which brain transcriptomes were analyzed (Mayo, ROSMAP, Mount Sinai) [50, 51], 2 cohorts that analyzed circulating exRNAs [8], and 4 additional cohorts that analyzed brain protein levels [53–55].

A Hypothetical Model of PHGDH’s Role in AD Etiology Our hypothetical model for the relevance of PHGDH to AD is as follows. PHGDH catalyzes serine biosynthesis in the brain, which is required for glycine production, as shown in conditional knockout animals [63]. Glycine and serine are both agonists at the glycine binding site on NMDA receptors, which must be bound along with glutamate to induce calcium influx via this re- ceptor [63–65].

Overactivity of NMDA receptors can lead to ex- citotoxicity [66]. PHGDH is almost exclusively expressed in as- trocytes [67] where serine is initially synthesized and stored, whereas the D-serine isomer is found in neurons and microglia, predominantly in regions of the brain that coincide with NMDA receptor expression [68].

Both endogenous glycine and D-serine have been found to potentiate excitotoxicity [69, 70], and the increased release of these co-modulators have been linked to synaptic damage in a range of neuropathologies, including AD [71–74]. Consistent with this idea, increased D-serine in the CSF has shown potential to distinguish probable AD patients from controls [72].

Recently, the discovery of a self-amplifying feedforward loop between Ab-independent excessive activities in a fraction of neurons at early stages and Ab-mediated hyperactivation at late stages of AD adds to the complexity of AD-associated brain changes [75].

Because sustained baseline activation is required for initiating this vicious circle of excessive activation [75], increased PHDGH expression may theoretically represent a necessary step in the early presymptomatic disease stages, where both pre-existing baseline activation and subsequent ex- citotoxicity take place.

A Potential Companion Diagnosis for NMDA-Receptor Inhibitors In order to prevent excitotoxicity in AD, NMDA receptor inhibitors have been widely utilized as AD medications. Among them, mem- antine is an US Food and Drug Administration (FDA)-approved drug for AD treatment [76]. Unfortunately, the drug has limited ef- ficacy [77].

One explanation for the limited efficacy of memantine may be due to the inability to identify the subpopulation with NMDA receptor overactivity that may most benefit from this treat- ment approach. Currently, memantine is only approved for mod- erate-to-severe AD individuals [77].

Our data suggest that PHGDH exRNA levels in peripheral blood potentially identify pa- tients whose NMDA receptor activities in brain may be elevated, and if so, they may be more likely to respond to memantine and other NMDA-receptor inhibitors. Consequently, it may be very informative to test plasma PHGDH exRNA levels as a biomarker to predict treatment efficacy of memantine in AD individuals.
These data also point to the exploration of exRNA biomarkers for other neurological diseases. Activation of several other clas- ses of transposable elements has been reported in other neuro- degenerative diseases, including ALS [45, 78, 79].

It would be useful to examine whether those classes of transposons were also upregulated in plasma exRNA. Additionally, NMDA receptor overactivation is also a molecular feature of schizophrenia [80], ALS [81], epilepsy [82], and drug addiction [83, 84]. It would be useful to test whether temporal changes of plasma PHGDH are associated with these disorders.



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