THE EFFECTS OF ALZHEIMERS-DISEASE, OTHER DEMENTIAS, AND PREMORTEM COURSE ON BETA-AMYLOID PRECURSOR PROTEIN MESSENGER-RNA IN FRONTAL-CORTEX

There are conflicting data regarding alterations in beta-amyloid precu rsor protein (APP) mRNAs in Alzheimer's disease (AD). This may be due partly to variables such as agonal state and choice of control group. We have used in situ hybridization histochemistry to study expression of APP mRNAs, with and without the domain encoding the Kunitz protease inhibitor, in a way that overcomes some of the limitations of the cur rent data. Tissue from frontal cortex was collected at rapid autopsy f rom patients with AD or other cognitive impairments whose terminal pha se was prospectively assessed. There were three main findings. Firstly , the amount of APP mRNAs correlated strongly with glutamate decarboxy lase activity and was reduced in association with terminal pyrexia. Th ese correlations suggest that agonal state affects APP mRNA and, there fore, that differences in premortem course may contribute to the varyi ng changes in APP transcript abundance reported in AD. Secondly, a red uction of both forms of APP mRNA, normalized to polyadenylated mRNA, w as found in AD compared with normal controls and with non-AD dementias . This supports findings that the APP-related pathology of AD is not d ue to overexpression of APP mRNA or an altered proportion of Kunitz pr otease inhibitor-containing isoforms. Thirdly, the amount of APP mRNA correlated inversely with that of heat-shock protein (hsx70) mRNA. Thi s relationship was unexpected given current theories that APP expressi on occurs as part of a stress response, and suggests that other factor s predominate in determining neocortical APP mRNA content in neurodege nerative disorders.