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

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.

Cognitive-enhancing effects of hydrolysate of polygalasaponin in SAMP8 mice

“…Reports have indicated that the function of NMDARs decreases in AD, including gene expression (Yashiro and Philpot, 2008), levels of mRNA and protein (Hynd et al, 2001), or neurotransmitters (Rupsingh et al, 2011). A decline in levels of NMDAR subunits has been observed in many AD models and clinical research (Hynd et al, 2004;Mishizen-Eberz et al, 2004;Kravitz et al, 2013), which is consistent with our result that NMDAR1 and NMDAR2B expression decreased in SAMP8 as compared with SAMR1 mice. The decreased level of NMDAR limited its normal functional role, leading to a deficit in learning and memory.…”

Characterization of Human Hippocampal Neural Stem/Progenitor Cells and Their Application to Physiologically Relevant Assays for Multiple Ionotropic Glutamate Receptors

“…15,16 The hippocampus plays important roles in the consolidation of information from short-term memory to long-term memory and in spatial learning; it is also a brain region central to neurological disorders such as AD, schizophrenia, and epilepsy. Kravitz et al 10 showed that the density of NMDARs was decreased in the postmortem human hippocampus in patients with AD; loss of NMDARs was 11 reported that AMPAR-mediated neurotransmission was increased in hippocampal CA3−CA1 synapses of an animal model of schizophrenia, the sandy mouse, contributing to inappropriate encoding of memory. Hippocampal sclerosis is commonly observed in patients with temporal lobe epilepsy (TLE).…”

“…The hippocampus is an important brain region involved in neurological disorders such as AD, schizophrenia, and epilepsy. [10][11][12][13] Therefore, we need to develop an assay system that uses human hippocampal neurons so that we can obtain a detailed understanding of the molecular mechanisms underlying these diseases and discover novel drugs for treating them.…”

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

“…Interestingly, a significant reduction of the density of NMDAR has been detected in AD neocortex and hippocampus, where Aβ deposition is heavy [85–87], which may underlie NMDAR hyposensitivity in the late stage of AD. In consistent with the influence of glutamatergic toxicity on synaptic function, memantine, a glutamate receptor antagonist has demonstrated some modest protection of memory loss in AD patients [88–90].…”