ABERRANT EXPRESSION OF THE CONSTITUTIVE ENDOTHELIAL NITRIC-OXIDE SYNTHASE GENE IN ALZHEIMER-DISEASE

Neuritic pathology is a major neuroanatomical correlate of dementia in Alzheimer disease (AD). Nitric oxide (NO) is linked to neuritic growt h and synaptic plasticity. Expression of one of the enzymes responsibl e for NO synthesis, the constitutive endothelial NO synthase (ceNOS), was investigated in brains of AD and Down syndrome patients using RNas e protection assays, in situ hybridization, and immunocytochemistry. I n end-stage AD, ceNOS expression was reduced in cortical neurons, and the enzyme was aberrantly translocated to membranes of proliferated sw ollen or collapsed neuritic processes. In addition, ceNOS expression w as strikingly increased in glial cells characterized mainly as protopl asmic (Type 2) astrocytes, which are responsible for maintaining the s tructural and functional integrity of cell processes in the CNS. In Do wn syndrome, similar abnormalities emerged by the third decade, preced ing the cognitive decline and establishment of CERAD criteria for AD, indicating that aberrant ceNOS expression occurs early in the course o f neurodegeneration. The results suggest that aberrant ceNOS transloca tion and gene regulation may have important roles in the pathogenesis of AD neuritic pathology.