NMDA receptor and PSD-95 expression in Alzheimer's disease play a role in postsynaptic alterations of frontal and cingulate cortex related to some clinical scores

Synaptic alterations in Alzheimer's disease are known to go along with cognitive deterioration but the morphological substratum is less well known. Postsynaptic reorganization was strongly suggested by an increase in cortical postsynaptic PSD-95 protein expression. Compensatory phenomena and/or impaired protein degradation represent likely hypotheses. To further understand synaptic changes, we now study the expression of NMDA receptors subunits in the frontal (FC9), anterior cingulate (CG24) and subgenual (CG25) areas. We used semi-quantitative and quantitative immunohistochemical methods for the estimation of Aß, phosphorylated Tau (AD2), synaptophysin, PSD-95 and NMDA receptor subunits R1, R2A and R2B in FC9, CG24 and CG25 from 24 control and AD cases. For nine AD cases correlations were studied between pathological data including Braak stages and scores to Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR) and Neuropsychiatric Inventory (NPI). Frontal and cingulate areas are significantly affected by Aß deposits and AD2 stained NFT in AD cases and CG25 appears more affected. However, neither Aß nor AD2 or Braak stages were significantly correlated to clinical scores. In all three regions, while synaptophysin expression indicates little changes, a significant increase in NMDAR1 subunit expression is shown, particularly in positive neurons, correlated to the increase in PSD-95. Colocalization between NMDAR1 and PSD-95 is observed in neurons often positive for AD2. On the contrary, NMDAR2A subunit expression is decreased and NMDAR2B more or less stable. Correlations of PSD-95 and NMDAR1 expression with MMSE, CDR and NPI scores appear stronger in CG25 than in other areas. Taken together, these data demonstrate that subgenual area 25 is more damaged than areas 24 and 9, but that Aß and NFT do not seem good correlates of clinical scores. On the contrary, postsynaptic parameters directly involved in memory processes, such as NMDAR1 and PSD-95 increased expression, appear to correlate with clinical scores, including NPI in subgenual area 25. This highlights the role of the postsynaptic protein PSD-95 and of NMDA receptors for synaptic plasticity in Alzheimer's disease, particularly in a region playing an important role in mood and behavior.