Alzheimer’s disease (AD) is a neurological disorder affecting > 6% of adults over 65 years of age, with an estimated global economic cost of 818 billion $ (in 2015). The disease is characterized by progressive memory loss and cognitive impairment. The pathophysiology involves extracellular accumulation of β-amyloid (Aβ) aggregates, intracellular neurofibrils, synaptotoxicity, gliosis, loss of neurons and brain atrophy.
Various experimental evidences link D-serine and AD. Excitotoxicity depends on NMDA receptor activation, which requires the action of a coagonist at a glutamate-binding site and a coagonist at the glycine-binding site. Synaptic loss is involved in AD pathophysiology, and a possible causal role can be due to glutamatergic dysfunction: neurotoxicity induced by Aβ is exacerbated by the release of NMDAR co-agonists, such as D-serine.
The seminal paper from (Wu et al., 2004) reported that neurotoxicity induced on primary hippocampal neurons cells by a primary microglia-conditioned medium treated with 15 µM Aβ (and thus enriched of D-serine) was rescued when the medium was depleted of D-serine by treatment with D-amino acid oxidase (DAAO), as well as by adding DKCA, an antagonist of the glycine modulatory site of NMDA receptor. Later on, the same group reported that APP (amyloid precursor protein) increased the level of serine racemase (SR, the enzyme deputed to D-serine synthesis) on microglia cells, probably acting at the transcriptional level (Wu et al., 2007).
SR knockout mice, holding a 90% decrease in forebrain D-serine content, also showed a reduced neurotoxicity induced by NMDA and Aβ peptide injections in forebrain (Inoue et al., 2008). These authors concluded “the control of SR activity and D-serine level in the brain may lead to a novel strategy for neuroprotection against various neurodegenerative diseases”.
A further link between D-serine and AD onset originates from the treatment with the well-known DAAO inhibitor sodium benzoate for 24 weeks of individuals with amnestic mild cognitive impairment or mild AD. Sodium benzoate produced a better improvement than placebo in AD assessment scale-cognitive subscale, additional cognition composite and clinician interview (Lin et al., 2014). The benefit of DAAO inhibition in AD might be mediated by an antioxidant effect due to prevention of hydrogen peroxide generation by the enzymatic degradation of D-serine. Notably, increased DAAO levels were observed in peripheral blood of patients with AD or mild cognitive impairment: the severity of cognitive impairment is higher at higher DAAO levels (Lin et al., 2017).
In the cortex of adult APP knockout mice, spine formation and elimination were decreased (while total spine density remained unaltered), and under environmental enrichment conditions the same mice failed to respond with an increase in spine density (Zou et al., 2016). Extracellular D-serine concentration was reduced in APP knockout mice while total serine was increased. The deficits of spine dynamics, adaptive plasticity, and morphology observed in these mice was restored by a chronic treatment with exogenous D-serine, as well as the cognitive deficit. These authors proposed that APP regulates homeostasis of D-serine, thus maintaining the constitutive and adaptive plasticity of dendritic spines in adult brain.
The observed increase in D-serine level in CSF of AD patients (see below) might represent a protective mechanism to counter Aβ signalling and prevent AD pathology. D-Serine increases neurogenesis and survival in neurons and regulates apoptosis: apoptosis is inhibited by the neuromodulator during its early phases while it is stimulated in later phases (Esposito et al., 2012). The increase in D-serine level in the early phases of AD might be therapeutically beneficial.
Is D-serine a suitable biomarker for AD?
Diagnosis of AD is based on neuropsychological tests, fluid biomarker assessment and brain imaging: diagnosis of the early stages of the disease is still a challenging.
In hippocampus and parietal cortex of AD patients the D-serine level was reported to be increased compared to healthy individuals (Madeira et al., 2015), as well as the SR and D-serine levels in models of AD. Indeed, the level of the neuromodulator were higher in the cerebrospinal fluid (CSF) of AD patients than in non-cognitively impaired control. These authors concluded that combination of D-serine level and Aβ/tau index increased the sensitivity and specificity of diagnosis at probable AD (Madeira et al., 2015). The conclusion of a D-serine increase in serum of AD patients was confirmed by (Lin et al., 2017; L. Pollegioni, unpublished results).
For sake of honesty, a slight decrease in D-serine level in serum was reported by (Hashimoto et al., 2004), and (Biemans et al., 2016) concluded that D-serine level in CSF of AD patients did not differ from other dementias and was also not correlated to minimental state examination scores.
As recently highlighted (Mothet et al., 2019), D-serine detection/quantification in biological samples needs of dedicated technologies and well-suited controls. The use of such good practices will help to establish whether D-serine is a suitable biomarker for AD and for cognitive decline.
Hashimoto K, Fukushima T, Shimizu E, Okada S, Komatsu N, Okamura N, Koike K, Koizumi H, Kumakiri C, Imai K, Iyo M. (2004) Possible role of D-serine in the pathophysiology of Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 28(2):385-8.
Inoue R, Hashimoto K, Harai T, Mori H (2008) NMDA- and beta-amyloid1–42-induced neurotoxicity is attenuated in serine racemase knock-out mice. J Neurosci 28:14486–14491
Lin C-H, Chen P-K, Chang Y-C, Chuo L-J, Chen Y-S, Tsai GE, et al. (2014) Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 75:678–85. doi:10.1016/j.biopsych.2013.08.010
Lin C-H, Yang H-T, Chiu C-C, Lane H-Y. (2017) Blood levels of D-amino acid oxidase vs. D-amino acids in reflecting cognitive aging. Sci Rep. 7:14849. doi:10.1038/s41598-017-13951-7
Esposito S, Pristerà A, Maresca G, Cavallaro S, Felsani A, Florenzano F, et al. (2012) Contribution of serine racemase/D-serine pathway to neuronal apoptosis. Aging Cell. 11:588–98. doi:10.1111/j.1474-9726.2012.00822.x
Madeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brandão CO, Reis T, et al. (2015) D-serine levels in Alzheimer’s disease: implications for novel biomarker development. Transl Psychiatry 5:e561. doi:10.1038/tp.2015.52
Mothet JP, Billard JM, Pollegioni L, Coyle JT, Sweedler JV. (2019) Investigating brain D-serine: Advocacy for good practices. Acta Physiol. 16:e13257. doi: 10.1111/apha.13257.
Wu SZ, Bodles AM, Porter MM, Griffin WS, Basile AS, Barger SW (2004) Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide. J Neuroinflammation 1:2. doi:10.1186/1742-2094-1-2
Wu S, Basile AS, Barger SW (2007) Induction of serine racemase expression and D-serine release from microglia by secreted amyloid precursor protein (sAPP). Curr Alzheimer Res. 4:243–251
Zou C, Crux S, Marinesco S, Montagna E, Sgobio C, Shi Y, Shi S, Zhu K, Dorostkar MM, Müller UC, Herms J (2016) Amyloid precursor protein maintains constitutive and adaptive plasticity of dendritic spines in adult brain by regulating D-serine homeostasis. EMBO J. 35(20):2213-2222.
Loredano Pollegioni, Università degli studi dell’Insubria