Abstract
d-Serine acts as a co-agonist of N-methyl-d-aspartate receptors (NMDAR) which appear overactivated in AD, while d-aspartate is a modulatory molecule acting on NMDAR as a second agonist. The aim of this work is to clarify whether the levels of these d-amino acids in serum are deregulated in AD, with the final goal to identify novel and precocious biomarkers in AD. Serum levels of l- and d-enantiomers of serine and aspartate were determined by HPLC using a pre-column derivatization procedure and a selective enzymatic degradation. Experimental data obtained from age-matched healthy subjects (HS) and AD patients were statistically evaluated by considering age, gender, and disease progression, and compared. Minor changes were apparent in the serum l- and d-aspartate levels in AD patients compared to HS. A positive correlation for the d-serine level and age was apparent in the AD cohort. Notably, the serum d-serine level and the d-/total serine ratio significantly increased with the progression of the disease. Gender seems to have a minor effect on the levels of all analytes tested. This work proposes that the serum d-serine level and d-/total serine ratio values as novel and valuable biomarkers for the progression of AD: the latter parameter allows to discriminate CDR 2 and CDR 1 patients from healthy (CDR 0) individuals.
Highlights
Alzheimer’s disease (AD), the most common cause of late-onset dementia, is a chronic and progressive neurodegenerative disease affecting ≈6% of adults over 65 years of age[1]
AD was diagnosed according to the NIA-AD criteria[3] and the disease stage of AD patients was assessed by using the Clinical Dementia Rating (CDR) Scale that allows to characterize five domains of cognitive and functional performance in AD dementia
Age-related variation of the investigated amino acids was analyzed by Spearman non-parametric correlation analyses (Supplementary Fig. 1): the D- and L-Asp levels and D-/total-Asp ratio did not significantly vary with age, neither in samples from healthy subjects (HS) nor from AD patients (D-Asp HS: r = 0.216, P = 0.2891; D-Asp AD: r = 0.02573, P = 0.8715; L-Asp HS: r = 0.03024, P = 0.8834; L-Asp AD: r = −0.2589, P = 0.8707; D-/total-Asp ratio HS: r = 0.1133, P = 0.5814; D-/total-Asp ratio AD: r = 0.02715, P = 0.8645)
Summary
Alzheimer’s disease (AD), the most common cause of late-onset dementia, is a chronic and progressive neurodegenerative disease affecting ≈6% of adults over 65 years of age[1]. The preliminary diagnosis of AD is made by a combination of clinical criteria, which includes neurological examinations, mental status tests, and brain imaging. On the basis of these clinical tests only, diagnosis of AD becomes a difficult task, especially in the early pre-symptomatic phase of the disease. AD pathophysiology is characterized by the accumulation of extracellular amyloid β (Aβ) plaques and intraneuronal inclusions of the truncated and phosphorylated forms of tau protein (neurofibrillary tangles). This appears to induce dystrophic neurites, loss of synapses, a prominent gliosis (involving changes in the morphology and function of microglia and astrocytes) and, only at later stages, overt loss of neurons and associated brain atrophy[5]. Consistent with the role of the glutamatergic system in learning and memory formation, alterations in
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