Neuromodulator D-serine as a Prime Target for Novel Neuroprotective Strategies

Professor Herman Wolosker
Prince Center Director

Accumulation of amyloid-β (Aβ) is thought to play a role in the pathology of Alzheimer’s disease (AD). Aβ oligomers are increasingly recognized as key mediators of synaptic and cognitive dysfunction in AD, and emerging evidence indicates that they affect the function of a key receptor in the brain, the NMDAR. In addition to being required for normal neurotransmission, NMDARs play a major role in neurodegeneration. Their excessive activation leads to an increase in intracellular calcium and activation of degenerative processes that contribute to cell death. In AD, accumulation of Aβ potentiates NMDAR-mediated neurodegeneration, but the exact mechanisms remain unknown.

For their normal operation, NMDARs require the binding of a novel type of transmitter, called D-serine. Our laboratory is among the pioneers in studying the role of D-serine by showing that this molecule is made in brain cells, and released to activate NMDARs, especially during neurotoxicity. D-serine is produced by a protein called serine racemase (SR), which seems to be a prime target for age-related memory deficits and neuroprotective strategies. Mice with targeted deletion of SR (SR knock-out mice), which cannot make D-serine, are highly resistant to neuronal damage by Aβ in vivo and are less susceptible to stroke upon occlusion of the middle cerebral artery. Furthermore, a mutation that inactivates D-amino acid oxidase, a protein that destroys D-serine in the spinal cord, causes a familial form of ALS (Lou Gehrig’s disease). Patients with this mutation have increased D-serine in their spinal cord and neurodegeneration. In sum, the data indicate that D-serine has a role in neurodegeneration, such as that seen in AD.

We expect this research to contribute to our understanding of brain-wide structural and functional alterations during the degeneration of brain cells, and potentially reveal novel markers of degeneration that precede the characteristic symptoms of Alzheimer’s disease. Within this framework, we propose to study the mechanisms by which Aβ affects D-serine dynamics in the brain, and whether NMDAR dysfunction, thought to play a role in neurodegeneration, is mediated by altered D-serine homeostasis.Herman Wolosker

Preliminary data in the literature indicate that Aβ increases D-serine release, but the mechanisms and pathogenic Aβ species involved are unknown. We will study the neurotoxic effects of different types of Aβ oligomers, and mechanisms affecting D-serine dynamics in new mice models, including mice lacking D-serine (SR-KO) and mice lacking putative D-serine transporters (Asc1 and ASCT1-KO mice) that are bred in our laboratory. Inhibitors of D-serine production or release constitute a new neuroprotective strategy, with implications for AD treatment.