Hippocampal Glutamate NMDA Receptor Loss Tracks Progression in Alzheimer’s Disease: Quantitative Autoradiography in Postmortem Human Brain

Efrat Kravitz,Inna Gaisler-Salomon,Anat Biegon,Christopher Mark Norris

doi:10.1371/journal.pone.0081244

Efrat Kravitz, Inna Gaisler-Salomon + Show 2 more

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https://doi.org/10.1371/journal.pone.0081244

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Abstract

Early Alzheimer's disease (AD) is characterized by memory loss and hippocampal atrophy with relative sparing of basal ganglia. Activation of glutamate NMDA receptors in the hippocampus is an important step in memory formation. We measured the density of NMDA receptors in samples of hippocampus, entorhinal cortex and basal ganglia obtained from subjects who died with pathologically confirmed AD and age- and sex- matched non-demented controls. We found significant decreases in NMDA receptor density in the hippocampus and entorhinal cortex but not in the basal ganglia. Loss of NMDA receptors was significantly correlated with neuropathological progression as assessed by Braak staging postmortem. The same samples were probed for neuroinflammation by measuring the density and gene expression of translocator protein 18kDA (TSPO), an established marker of microglial activation. Unlike NMDA receptor loss, increased densities of TSPO were found in all of the brain regions sampled. However hippocampal, but not striatal TSPO density and gene expression were inversely correlated with NMDA receptor density and positively correlated with Braak stage, suggesting NMDA receptors exacerbate neuroniflammatory damage. The high correlation between hippocampal NMDA receptor loss and disease progression supports the use of non invasive imaging with NMDA receptor tracers and positron emission tomography as a superior method for diagnosis, staging and treatment monitoring of AD in vivo.

Highlights

Despite decades of research, the etiology of sporadic Alzheimer’s disease, a progressive neurodegenerative disorder primarily affecting memory [1] and characterized by progressive deposition of neurofibrillary tangles and amyloid plaques in hippocampal and cortical regions [2], is still unknown
Employing quantitative in vitro autoradiography with the specific N-methyl-DAspartate receptors (NMDAR) antagonist [3H]MK801, we have examined the regional density of NMDAR in the hippocampal formation, entorhinal cortex and basal ganglia of subjects (N=23) who died with Alzheimer's disease (AD) and 17 age- and sex matched non-demented controls (Table 1)
We found significant decreases in NMDAR in hippocampal fields and in the entorhinal cortex, which contain pyramidal neurons, but not in the dentate gyrus, which is composed primarily of granular cells, or the basal ganglia (Figure 1)

Summary

Introduction

The etiology of sporadic Alzheimer’s disease, a progressive neurodegenerative disorder primarily affecting memory [1] and characterized by progressive deposition of neurofibrillary tangles and amyloid plaques in hippocampal and cortical regions [2], is still unknown. Postmortem studies have found reduced NMDAR density and gene expression in cortex and hippocampus of AD patients [11,12]; there was no attempt to examine other brain regions or to correlate the loss of NMDAR with histopathology, ApoE genotype [13] or other relevant imaging targets such as microgliosis [14,15].

Results

Conclusion