QUANTIFICATION OF APP AND APLP2 MESSENGER-RNA IN APOE GENOTYPED ALZHEIMERS-DISEASE BRAINS

Amyloid precursor protein (APP) is metabolised to produce A beta, a pe ptide found aggregated in Alzheimer's disease neuritic plaques. APP is a member of a multigene protein family which includes amyloid precurs or-like protein 2 (APLP2). Since A beta accumulation can be triggered by factors acting up- or downstream of APP processing, we investigated whether APP mRNA expression was altered in Alzheimer's disease post-m ortem cerebral cortex. In addition, we characterised cortical APLP2 mR NA levels. Quantitative RNA-RNA solution hybridisation-RNase protectio n was used to assay total APP, APP containing the Kunitz-type protease inhibitor (KPI) insert and APLP2 mRNA in mid-temporal and superior fr ontal cortices from apolipoprotein E-genotyped subjects with Alzheimer 's disease, other neurological diseases and non-demented controls. App roximately 3 times more APP than APLP2 mRNA was detected and about 70% of total APP mRNA contained the KPI insert in the control subjects. T otal APP and APLP2 mRNA levels were significantly reduced in Alzheimer 's disease mid-temporal, but not superior frontal cortex, suggesting t hat regional reductions in these mRNAs correlate with severity of dise ase pathology. A small significant increase in the proportion of APP K PI mRNA was seen in both cortical regions in Alzheimer's disease. Apol ipoprotein E genotype did not: influence cortical levels of total APP, APP KPI or APLP2 mRNA. Alzheimer's disease-related increases in tissu e DNA content were seen in both regions studied, while tissue RNA leve ls were reduced in the positive disease controls. In summary, these re sults indicate that Alzheimer's disease is not associated with over-ex pression of either APP or APLP2 mRNA. Our findings reveal a disease-as sociated increase in the proportion of APP KPI-containing isoforms, an d further investigation should clarify whether this predisposes affect ed individuals to A beta production and aggregation, or reflects later events such as gliosis and neuronal cell death.