Amyloid precursor protein gene isoforms in Alzheimer's disease and other neurodegenerative disorders

Differential expansion of the amyloid precursor protein gene (APP) may be i mportant in the development of amyloidosis in Alzheimer's disease (AD) and experimentally in the brain's response to injury. Controversial data sugges ts that APP isoforms containing the Kunitz protease inhibitor isoform (APP KPI+) are over expressed in the brains of patients with AD when compared to the non-Kunitz protease inhibitor containing isoforms (APP KPI-). We have investigated this hypothesis using a quantitative analysis of gene expressi on on brain tissue collected at post-mortem. In situ hybridization has been used with synthetic oligonucleotide probes labelled with S-35 to detect th e two principal splice variants of APP: APP 695 (KPI-) and APP 751 (KPI+). A prospective brain bank of frozen brain specimens has been established and includes pathologically proven AD (n=15) and other neurodegenerative disor ders as controls (n=18). The controls consist of frontal lobe atrophy (n=4) , Huntington's disease (n=5), Parkinson's disease (n=4), motor neuron disea se (n=2), multi-infarct dementia (n=1), multisystem atrophy (n=1), and suba cute sclerosing panencephalitis (n=1). We have observed no significant diff erences in the expression of APP 695 KPI- mRNA in frontal lobe: 17.49+/-3.2 6 optical density (OD) units of mRNA expression in AD vs. 16.13+1.76 OD uni ts mRNA in controls (P=0.80, linear regression); or temporal lobe: 14.73+/- 2.96 in AD vs. 16.49+/-2.15 in controls (P=0.55). No significant difference s have been found in APP 751 KPI+ in frontal lobe: 12.86+/-2.98 in AD vs. 1 3.70+/-2.88 in controls (P=0.97); and temporal lobe: 13.31+/-4.93 in AD vs. 11.07+/-1.99 in controls (P=0.65). Analysis of the ratios of APP 751 KPIOD units of mRNA to APP 695 KPI- mRNA revealed a trend to an increased rati o which did not reach statistical significance: frontal lobe APP 751 KPI+/A PP 695 KPI- 1.92+/-1.04 in AD vs. 0.86+/-0.17 in controls (P=0.54); tempora l lobe 2.54+/-1.59 in AD vs. 0.96+/-0.11 controls (P=0.34). Our data has no t revealed differential expression of APP mRNA isoforms in AD and supports the hypothesis that post-translational events in APP metabolism are importa nt in amyloidogenesis and the pathogenesis of AD. (C) 2000 Elsevier Science B.V. All rights reserved.