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S084-2

Establishing Peripheral Biomarkers for Cognitive Aging – Approach from
N-Methyl-D-Aspartate Neurotransmission Pathway

Chieh-Hsin Lin

China Medical University, Taiwan

Background/Objective: The increasing prevalence of dementia in the elderly is a heavy burden of
both patients and their family. To date, the diagnosing of Alzheimer’s disease (AD) or mild cognitive
impairment (MCI) relies mainly on clinical manifestation. Favourable peripheral laboratory tests are
lacking. N-methyl-D-aspartate (NMDA) activation plays an important role in learning and memory.
NMDA-glycine site enhancers were also found to have positive effect in the Drosophila model of
AD. We have found that NMDA enhancer-benzoate can significantly improve the cognitive function
of patients with early-phase AD. Genes associated with modulating NMDA function may be
involved in the etiology of AD and MCI.

Method: We have established the model of measuring the mRNA/protein expression of
NMDA-related genes, including D-amino acid oxidase (DAO), D-amino acid oxidase activator
(DAOA, or named G72) and Serine racemase (SRR). DAO is one of the genes on the pathway
associated with modulating NMDA function. DAO can metabolize D-amino acids, such as D-serine,
which plays an important role in proliferation and neuronal differentiation of neural stem cells. In
addition, a body of evidence suggests that DAO also plays a key role in the process of oxidative
stress.

Result: We found that the peripheral DAO levels were higher in the patients with early-phase AD
and in the healthy elderly individuals than in the healthy non-elderly adults. Moreover, there was a
positive correlation between age and DAO level in the healthy non-elderly adults and healthy elderly
individuals. Our previous study revealed that the plasma G72 protein levels in patients with
schizophrenia were distinctively higher than that of healthy individuals.

Conclusion: The findings suggest that DAO level has a potential to be a biomarker for aging. We
also hypothesize that other NMDA-related gene expressions in the peripheral blood may predict
age-related cognitive decline for AD and MCI.

Reference: Lin CH et al. NMDA Neurotransmission Dysfunction in Mild Cognitive Impairment
and Alzheimer’s disease. Current Pharmaceutical Design. 2014; 20(32):5169-5179.
Lin CH et al. Distinctively higher plasma G72 protein levels in patients with schizophrenia than in
healthy individuals. Molecular Psychiatry. 2014 Jun; 19(6):636-637.