Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease

Abstract

Previous work had shown that the ratio of NMDA receptor NR1 subunit mRNA transcripts containing an N-terminal splice cassette to those that do not is markedly lower in regions of the Alzheimer's disease (AD) brain that are susceptible to pathological damage, compared with spared regions in the same cases or homotropic regions in controls. To elucidate the origins of this difference in proportionate expression, we measured the absolute levels of each of the eight NR1 transcripts by quantitative internally standardized RT-PCR assay. Expression of transcripts with the cassette was strongly attenuated in susceptible regions of Alzheimer's brain, whereas expression of non-cassette transcripts differed little from that in controls. The expression of other NR1 splice variants was not associated with pathology relevant to disease status, although some combinations of splice cassettes were well maintained in AD cases. The population profile of NR1 transcripts in occipital cortex differed from the profiles in other brain regions studied. Western analysis confirmed that the expression of protein isoforms containing the N-terminal peptide was very low in susceptible areas of the Alzheimer's brain. Cells that express NR1 subunits with the N-terminal cassette may be selectively vulnerable to toxicity in AD. Keywords: Alzheimer's disease, excitotoxicity, glutamate, N-methyl-D-aspartate, polyamine. NMDA receptors (NMDARs) are present on most CNS neurones (Petralia et al. 1994) and mediate Ca 2+ influx in response to glutamate (Constantine-Paton 1990;Bliss and Collingridge 1993;Seeburg 1993;Hollmann and Heinemann 1994;Constantine-Paton and Cline 1998). Their excessive activation has been implicated in hypoxia-ischemia, epilepsy, and chronic neurodegenerative disorders such as Huntington's and Alzheimer's diseases (Choi 1988;Young 1993;Olney 1994;Chen et al. 1999). The impairments in memory and cognition in Alzheimer's disease (AD) can be correlated to the neuropathological features of the disease, including neuronal loss and plaque and tangle formation in the cortex and hippocampus (Hyman et al. 1986; Albin and Greenamyre 1992; Bobinski et al. 1998). Neuronal loss is generally restricted to the pyramidal cells in layers III and IV. Damage to glutamate-innervated neurones is also observed (Albin and Greenamyre 1992). Axons, terminal boutons, glia, and endothelial and ependymal cells are relatively spared (Choi 1992).NMDARs are heteromeric assemblies comprising a ubiquitous NR1 subunit and two or more NR2 subunits (NR2 A-D) (Monyer et al. 1992;Ishii et al. 1993;Dingledine et al. 1999). An NR3 subunit has also been cloned (Sucher et al. 1995;Das et al. 1998). The function and modulation of NMDAR channels is spatially and temporally regulated (Bockers et al. 1994;Rigby et al. 1996). While the NR1 subunit is expressed ubiquitously, NR2 subunits show regional and developmental variations (Watanabe et al. 1992(Watanabe et al. , 1993Akazawa et al. 1994;Monyer et al. 1994). The NR1 subunit undergoes alternate splicing of three ex...

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