Title:Serine Racemase Expression Differentiates Aging from Alzheimer’s Brain
Volume: 19
Issue: 7
Author(s): Shengzhou Wu*, Jing Zhou, He Zhang and Steven W. Barger*
Affiliation:
- School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, State Key Laboratory of
Optometry, Wenzhou, Zhejiang 325003, P.R. China
- Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock
AR, USA
- Geriatric Research, Education & Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock
AR, USA
Keywords:
Hippocampus, neural network, mild cognitive impairment, long-term potentiation, neurotransmission, synaptic plasticity, ERK, CaMKIV.
Abstract: Aging is an inevitable process characterized by progressive loss of physiological integrity
and increased susceptibility to cancer, diabetes, cardiovascular, and neurodegenerative diseases; aging
is the primary risk factor for Alzheimer’s disease (AD), the most common cause of dementia. AD is
characterized by brain pathology, including extracellular deposition of amyloid aggregation and intracellular
accumulation of neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition,
losses of synapses and a wide range of neurons are pivotal pathologies in the AD brain. Accumulating
evidence demonstrates hypoactivation of hippocampal neural networks in the aging brain,
whereas AD-related mild cognitive impairment (AD-MCI) begins with hyperactivation, followed by a
diminution of hippocampal activity as AD develops. The biphasic trends of the activity of the hippocampal
neural network are consistent with the alteration of N-methyl-D-aspartate receptor (NMDA-R)
activity from aging to prodromal (AD-MCI) to mid-/late stage AD. D-serine, a product of racemization
catalyzed by serine racemase (SR), is an important co-agonist of the NMDA-R which is involved
in synaptic events including neurotransmission, synaptogenesis, long-term potentiation (LTP), development,
and excitotoxicity. SR and D-serine are decreased in the hippocampus of the aging brain, correlating
with impairment of cognitive function. By contrast, SR is increased in AD brain, which is associated
with a greater degree of cognitive dysfunction. Emerging studies suggest that D-serine levels
in the brain or in cerebral spinal fluid from AD patients are higher than in age-matched controls, but
the results are inconsistent. Very recently, serum D-serine levels in AD were reported to correlate with
sex and clinical dementia rating (CDR) stage. This review will discuss alterations of NMDA-R and SR
in aging and AD brain, and the mechanisms underlying the differential regulation of SR will be
probed. Collectively, we propose that SR may be a molecular switch that distinguishes the effects of
aging from those of AD on the brain.