Madeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brandão CO, Reis T, Leite RE, Laks J, Jacob-Filho W, Pasqualucci CA, Grinberg LT, Ferreira ST, Panizzutti R. d-serine levels in Alzheimer's disease: implications for novel biomarker development. Transl Psychiatry. 2015 May 5;5:e561. PubMed.

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    • User Profile Image Steve Barger
      University of Arkansas for Medical Sciences
    • Posted:

    Excitatory amino acids (EAA) have a long and complex history in AD research. Considerable evidence exists for EAA dysregulation in AD pathogenesis, including depletion of the so-called “glycineB” component of the NMDA receptor (Procter et al., 1989). Nevertheless, such evidence must be resolved in the context of a generalized hypoactivity in the AD brain, as well as the limited efficacy of memantine, an NMDA-receptor antagonist. These caveats are compounded by the fact that the direct impact of Aβ on excitatory synapses is predominantly inhibitory. The latter could belie a very different effect that is mediated indirectly through Aβ’s activation of glia. Microglia exposed to Aβ quickly begin to release substantial levels of glutamate via a chain of biochemical events that begins with the oxidative burst and ultimately involves the system-Xc glutamate/cystine antiporter (Barger et al., 2007). In addition to this early response, a somewhat slower induction of the gene for serine racemase can result in an order-of-magnitude elevation in production of dextrorotatory serine (Wu et al., 2004), now known to be the most relevant ligand for “glycineB” sites in the forebrain. The D-serine thus produced contributes significantly to the neurotoxicity that activated microglia exhibit in coculture with neurons, and serine racemase-knockout mice are less severely impacted by intracerebral injections of Aβ (Inoue et al., 2008). The serine racemase promoter was shown to be responsive to Jun-kinase activation in microglia via the AP-1 transcription factor (Wu et al., 2004). Together, the data suggest that serine racemase and its product provide a mechanistic link between neuroinflammation and neurodegeneration.

    Some years ago, a talented graduate student working in my laboratory, Shengzhou Wu, documented an elevated expression of serine racemase in AD temporal-lobe cortex (Wu et al., 2004). Madeira et al. have now reported that measurements of D-serine in the CSF can serve as a useful additional discriminator in AD diagnosis. Alone, [D-Ser]CSF proved more sensitive than the Aβ:Tau ratio; when coupled with the latter index, [D-Ser]CSF boosted specificity to essentially 100 percent. This report also makes several other useful contributions to our understanding of D-serine, including evidence of regional specificity of [D-Ser] in AD and rather impressive quantitative correlations between [D-Ser]CSF and AD staging (by MMSE and CDR). As the authors point out, this temporal and regional specificity may explain previous reports that failed to find a correspondence between AD and D-serine levels (Chouinard et al., 1993; Nagata et al., 1995). Serine racemase could be induced only transiently, elevating D-serine in a wave across the pathogenic progression from hippocampus to temporal neocortex and beyond; sampling of specific regions at the wrong time might miss the hypothetical wave. 

    This sort of conditional elevation of D-serine could also speak to the broader issues of excitatory amino acids and neuroinflammation in AD. Madeira et al. are careful to point out that D-serine is not wholly a bad thing. It is a deficiency in D-serine, not a glut, that appears to play a role in psychosis (Labrie et al., 2009); one must consider the possibility that elevation of this molecule after microglial activation represents part of a compensatory response. We would do well to remember that EAA stimulation can result in diminished electrophysiological activity. The classic work of John Olney, for instance, documented a role for such inhibition in the untoward effects of excitotoxins after their activation of GABAergic neurons (Olney et al., 1997). Likewise, acute elevations of glutamate, such as occur in ischemia or traumatic brain injury, can create a reactive downregulation of ionotropic glutamate receptors; remediation at later time points is effected not by glutamate-receptor antagonists but by agonists. One such agonist showing utility in preclinical models of acute excitotoxicity is D-cycloserine, a pharmacological cousin of D-serine. Another unexpected result came from an ALS mouse model, where elevation of D-serine hastened disease onset but also delayed progression (Thompson et al., 2012). This may reflect a delayed or secondary stage of disease that results not from hyperexcitation but from hyperinhibition (Schutz, 2005). Therefore, it is worth considering that serine racemase induction and other aspects of glial activation exist to supplant the trophic neurochemical activity otherwise reduced by Aβ. 

    References:

    Barger SW, Goodwin ME, Porter MM, Beggs ML. Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. J Neurochem. 2007 Jun;101(5):1205-13. Epub 2007 Mar 30 PubMed.

    Chouinard ML, Gaitan D, Wood PL. Presence of the N-methyl-D-aspartate-associated glycine receptor agonist, D-serine, in human temporal cortex: comparison of normal, Parkinson, and Alzheimer tissues. J Neurochem. 1993 Oct;61(4):1561-4. PubMed.

    Inoue R, Hashimoto K, Harai T, Mori H. NMDA- and beta-amyloid1-42-induced neurotoxicity is attenuated in serine racemase knock-out mice. J Neurosci. 2008 Dec 31;28(53):14486-91. PubMed.

    Labrie V, Fukumura R, Rastogi A, Fick LJ, Wang W, Boutros PC, Kennedy JL, Semeralul MO, Lee FH, Baker GB, Belsham DD, Barger SW, Gondo Y, Wong AH, Roder JC. Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. Hum Mol Genet. 2009 Sep 1;18(17):3227-43. Epub 2009 May 30 PubMed.

    Madeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brandão CO, Reis T, Leite RE, Laks J, Jacob-Filho W, Pasqualucci CA, Grinberg LT, Ferreira ST, Panizzutti R. d-serine levels in Alzheimer's disease: implications for novel biomarker development. Transl Psychiatry. 2015 May 5;5:e561. PubMed.

    Nagata Y, Borghi M, Fisher GH, D'Aniello A. Free D-serine concentration in normal and Alzheimer human brain. Brain Res Bull. 1995;38(2):181-3. PubMed.

    Olney JW, Wozniak DF, Farber NB. Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. Arch Neurol. 1997 Oct;54(10):1234-40. PubMed.

    Procter AW, Wong EH, Stratmann GC, Lowe SL, Bowen DM. Reduced glycine stimulation of [3H]MK-801 binding in Alzheimer's disease. J Neurochem. 1989 Sep;53(3):698-704. PubMed.

    Schütz B. Imbalanced excitatory to inhibitory synaptic input precedes motor neuron degeneration in an animal model of amyotrophic lateral sclerosis. Neurobiol Dis. 2005 Oct;20(1):131-40. PubMed.

    Thompson M, Marecki JC, Marinesco S, Labrie V, Roder JC, Barger SW, Crow JP. Paradoxical roles of serine racemase and d-serine in the G93A mSOD1 mouse model of amyotrophic lateral sclerosis. J Neurochem. 2012 Feb;120(4):598-610. PubMed.

    Wu S, Barger SW. Induction of serine racemase by inflammatory stimuli is dependent on AP-1. Ann N Y Acad Sci. 2004 Dec;1035:133-46. PubMed.

    Wu SZ, Bodles AM, Porter MM, Griffin WS, Basile AS, Barger SW. Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide. J Neuroinflammation. 2004 Apr 20;1(1):2. PubMed.

    View all comments by Steve Barger

  2. Ayton et al. published interesting data on CSF ferritin as a biomarker for AD. Based on the cognitive data, the authors conclude that ferritin is a trait marker because it correlates cross-sectionally with cognitive scores, but not with change in cognition over time. Still, they also observed that in MCI, baseline ferritin concentrations predicted progression to AD-type dementia, which seems to contradict the first finding. One possible explanation for the discrepancy is that in the first analysis both control and MCI subjects were included. The authors added diagnosis as a factor but did not report that they tested the interaction between diagnosis and change over time; previous studies clearly showed that cognitive change is different between controls and MCI subjects. Hence, it may be possible that a lack of prediction in cognitive change was because the controls improved in cognition at follow-up while MCI subjects declined. Another surprising finding is that ferritin did not differ between diagnostic groups, though it was associated with cognitive scores and also with AD biomarkers that all differ between diagnostic groups. Given the relatively strong correlation of increased ferritin with increased CSF tau and the weak association with increased CSF Aβ42, it may be possible that increased ferritin reflects neurodegeneration rather than an event associated with the onset of the disease. The current evidence seems insufficient to recommend studies on lowering brain iron, but rather emphasizes the need for further cross-sectional and longitudinal studies to define the role of iron in AD.

    The paper of Madeira et al. convincingly shows that D-serine is increased in AD, although the studies, based on CSF, had a relatively small sample size. D-serine correlated with a ratio of CSF Aβ42 and total tau providing additional support for the involvement of D-serine in AD. It would be of interest to see whether D-serine more strongly correlates with CSF tau or CSF Aβ42, as this would give an indication of whether D-serine reflects neuronal injury or amyloid aggregation.

    View all comments by Pieter Jelle Visser

  3. Following a suggestion posted by Pieter Jelle Visser, we have re-analyzed our data (Madeira et al., 2015) to examine individual correlations between CSF D-serine levels and Aβ42/tau/p-tau181 levels in AD and control individuals. The first conclusion from this re-analysis was that there is no correlation between CSF D-serine levels and p-tau181 levels (R2 = 0.0002; P = 0.46). The second conclusion was that there is indeed a negative correlation (R2 = 0.45; P < 0.0001) between CSF D-serine and Aβ42 levels, as might be expected if D-serine is up-regulated and released from neurons and/or glia in response to brain accumulation of Abeta oligomers and amyloid aggregation.

    Intriguingly, however, D-serine levels were positively correlated with total tau levels in the CSF (R2 = 0.37; P = 0.0008), which might indicate that, at least in part, elevation of D-serine in the CSF might be related to neurodegeneration. The overall correlation between the IATI index and D-serine levels that we reported thus appears to originate from both Aβ42 and total tau measures in CSF.

    We note, however, that the sample size used in this study was small. Results were robust when the IATI index was correlated with D-serine levels, but it is possible that the study was insufficiently powered to detect individual correlations between the various analytes in CSF. It will be interesting to further investigate the origin of the D-serine increase in CSF in a future study with a larger cohort of demented and control patients.

    References:

    Madeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brandão CO, Reis T, Leite RE, Laks J, Jacob-Filho W, Pasqualucci CA, Grinberg LT, Ferreira ST, Panizzutti R. d-serine levels in Alzheimer's disease: implications for novel biomarker development. Transl Psychiatry. 2015 May 5;5:e561. PubMed.

    View all comments by Mychael Lourenco

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