Excitotoxic neurodegeneration in Alzheimer's disease

Initial analysis of the expression profile of two NMDAR1 mRNA isoform subsets, NR1oxx and NR11xx, in discrete regions of human cerebral cortex was performed. The subsets are characterized by the absence or presence of a 21-amino acid N-terminal cassette. RT-PCR for NR1 isoforms was performed on total RNA preparations from spared and susceptible regions from pathologically confirmed Alzheimer disease (AD) cases and matched Controls. NR11xx transcript expression was calculated as a proportion of the NR11xx + NR10xx total. Values were significantly lower in AD cases than in Controls in mid-cingulate cortex, P < 0.01, superior temporal cortex, P < 0.01, and hippocampus, P ≈ 0.05. Cortical proportionate NR11xx transcript expression was invariant over the range of ages and areas of Controls tested, at ~50%. This was also true for AD motor and occipital cortices. Proportionate NR11xx expression in AD cingulate and temporal cortex was lower at younger ages and increased with age: this regression was significantly different from that in the homotropic areas of Controls. To elucidate the origins of this difference in proportionate expression, absolute levels of each of the eight NR1 transcripts was assessed by quantitative internally standardized reverse transcription polymerase chain reaction. Expression of transcripts with the cassette was strongly attenuated in susceptible regions of AD 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 AD brain.