The Effects of Alzheimer's Disease, Other Dementias, and Premortem Course on β‐Amyloid Precursor Protein Messenger RNA in Frontal Cortex

Abstract

There are conflicting data regarding alterations in ß-Amyloid precursor 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 current data . Tissue from frontal cortex was collected at rapid autopsy from patients with AD or other cognitive impairments whose terminal phase was prospectively assessed . There were three main findings . Firstly, the amount of APP mRNAs correlated strongly with glutamate decarboxylase activity and was reduced in association with terminal pyrexia . These correlations suggest that agonal state affects APP mRNA and, therefore, that differences in premortem course may contribute to the varying changes in APP transcript abundance reported in AD . Secondly, a reduction of both forms of APP mRNA, normalized to polyadenylated mRNA, was found in AD compared with normal controls and with non-AD dementias. This supports findings that the APP-related pathology of AD is not due to overexpression of APP mRNA or an altered proportion of Kunitz protease inhibitor-containing isoforms . Thirdly, the amount of APP mRNA correlated inversely with that of heat-shock protein (hsx70) mRNA . This relationship was unexpected given current theories that APP expression occurs as part of a stress response, and suggests that other factors predominate in determining neocortical APP mRNA content in neurodegenerative disorders . Key Words : Agonal state-Alzheimer's disease-ß-Amyloid-Gene expression-Heat shock-In situ hybridization-mRNA .

The ultimate chip shot: can microarray technology deliver for neuroscience?

“…In contrast to post-mortem factors, a great deal of variability appears to come from the premortem phase known as agonal state. Factors that contribute to this variability in gene expression include events such as coma (Harrison et al 1991), hypoxia (Burke et al 1991) and pyrexia (Harrison et al 1994;Morrison-Bogorad et al 1995). Given that the influence of the agonal state is difficult to predict for any given mRNA, it is critical to control for premortem conditions in any experimental design.…”

Human postmortem tissue: What quality markers matter?

“…Increasingly, human postmortem brain tissue is being used to quantify cellular and molecular markers of neural processes in the pursuit of understanding normal brain function and correlates of dysfunction in CNS illnesses (Casanova and Kleinman, 1990;Castensson et al, 2000;Harrison et al, 1994;Mirnics et al, 2001;Ravid et al, 1992;Torrey et al, 2000). Because of the inaccessibility of the human brain and its unavailability for biopsy, fresh tissue is rarely obtainable.…”

Relationships Between Expression of Apolipoprotein E and β-Amyloid Precursor Protein Are Altered in Proximity to Alzheimer β-Amyloid Plaques

“…Several familial AD lineages have now been identified in which a more restricted duplication results in a 50% increase in gene dosage for βAPP gene, strongly suggesting that duplication of the βAPP gene alone is sufficient to cause amyloid deposition and related dementia (6, 7). Nonetheless, some reports of mRNA or protein measurements show no overall elevation of βAPP in homogenates from AD brain (8, 9), and some have even reported a decrease (10, 11). …”