Amyloid precursor protein metabolism in fibroblasts from individuals with one, two or three copies of the amyloid precursor protein (APP) gene.

Protein kinase C (PKC)-activated modulation of amyloid precursor protein (APP) metabolism has been investigated in natural models of altered APP expression due to the presence of one, two or three copies of the APP gene. We show that levels of APP present in human skin fibroblasts strongly influence the effect of PKC activation of soluble APP (sAPP) release. Thus fibroblasts derived from a patient with a deletion in chromosome 21 including the APP locus (Delta21) had lower levels of both APP mRNA and cell-associated APP, and showed an exaggerated phorbol-ester-induced sAPP release, when compared with fibroblasts from control individuals. In contrast, fibroblasts from chromosome 21 trisomic Down's syndrome patients failed to show a concentration-dependent response to phorbol ester treatment. These results suggest that the levels of APP expression can affect the degree of response to PKC-mediated modulation of the metabolism of this protein.

Presenilin-1, amyloid precursor protein and amyloid precursor-like protein 2 mRNA levels in human superior frontal cortex during aging.

The presenilin-1 (PS-1) and amyloid precursor protein (APP) genes carry mutations which co-segregate with early-onset familial Alzheimer's disease. The APP and PS-1 gene products may be involved in the aetiology of the more common late onset form of Alzheimer's disease, where increasing age is a major risk factor. To investigate whether age affected mRNA expression of these genes, we quantified PS-1, total APP, APP containing the kunitz-type protease inhibitor (KPI) domain and amyloid precursor-like protein 2 (APLP2) mRNAs in post-mortem superior frontal cortices from 23 control subjects aged 38 to 89 years using solution hybridisation-RNase protection assays. PS-1, total APP, APP KPI and APLP2 mRNA levels were unchanged over this age range. PS-1 was the least abundant mRNA, at approximately 7% of total APP, the most highly expressed mRNA studied (10.8 copies/pg total RNA). The proportion of total APP encoding the KPI domain (approximately 52%) was unaffected by age. APLP2 mRNA was present at approximately 29% of the total APP mRNA level. Significant positive correlations were present between total APP, APP KPI and APLP2 mRNA levels. These results indicate that the increased prevalence of Alzheimer's disease cannot be attributed to alterations in cortical PS-1, APP and APLP2 mRNA levels or APP KPI splicing during aging.