Dysregulation of Amyloid-β Protein Precursor, β-Secretase, Presenilin 1 and 2 Genes in the Rat Selectively Vulnerable CA1 Subfield of Hippocampus Following Transient Global Brain Ischemia

Abstract

The interaction between brain ischemia and Alzheimer's disease (AD) has been intensively investigated recently. Nevertheless, we have not yet understood the nature and mechanisms of the ischemic episodes triggering the onset of AD and how they influence its slow progression. The assumed connection between brain ischemia and the accumulation of amyloid-β (Aβ) peptide awaits to be clearly explained. In our research, we employed a rat cardiac arrest model to study the changes in gene expression of amyloid-β protein precursor (AβPP) and its cleaving enzymes, β- and γ-secretases (including presenilins) in hippocampal CA1 sector, following transient 10-min global brain ischemia. The quantitative reverse-transcriptase PCR assay demonstrated that the expression of all above genes that contribute to Aβ peptide generation was dysregulated during 30 days in postischemic hippocampal CA1 area. It suggests that studied Aβ peptide generation-related genes can be involved in AβPP metabolism, following global brain ischemia and will be useful to identify the molecular mechanisms underpinning that cerebral ischemia might be an etiological cause of AD via dysregulation of AβPP and its cleaving enzymes, β- and γ-secretases genes, and subsequently, it may increase Aβ peptide production and promote the gradual and slow development of AD neuropathology. Our data demonstrate that brain ischemia activates delayed neuronal death in hippocampus in an AβPP-dependent manner, thus defining a new and important mode of ischemic cell death.

Keywords: Alzheimer’s disease; CA1 area; amyloid-β protein precursor; brain ischemia; dementia; genes; hippocampus; presenilin 1 and 2; β-secretase; γ-secretase.

Fig.1

The mean gene expression levels of presenilin 1 in the hippocampus CA1 area in rats 2, 7, and 30 days after 10-min of global brain ischemia. Marked SEM, standard error of the mean. Indicated statistically significant differences in levels of gene expression between 2 and 30 and between 7 and 30 days after 10-min of global brain ischemia (Mann-Whitney U test). ^*p≤0.005, ^**p≤0.0001.

Fig.2

The mean gene expression levels of presenilin 2 in the hippocampus CA1 area in rats 2, 7, and 30 days after 10-min of global brain ischemia. Marked SEM, standard error of the mean. Indicated statistically significant differences in levels of gene expression between 2 and 30 and between 2 and 7 and between 7 and 30 days after 10-min of global brain ischemia (Mann-Whitney U test). ^*p≤0.005, ^**p≤0.0001.

Fig.3

The mean gene expression levels of β-secretase in the hippocampus CA1 area in rats 2, 7, and 30 days after 10-min of global brain ischemia. Marked SEM, standard error of the mean. Indicated statistically significant differences in levels of gene expression between 2 and 30 and between 2 and 7 and between 7 and 30 days after 10-min of global brain ischemia (Mann-Whitney U test). ^*p≤0.002, ^**p≤0.0001.

Fig.4

The mean gene expression levels of amyloid-β protein precursor in the hippocampus CA1 area in rats 2, 7, and 30 days after 10-min of global brain ischemia. Marked SEM, standard error of the mean. Indicated statistically significant differences in levels of gene expression between 2 and 30 and between 2 and 7 and between 7 and 30 days after 10-min of global brain ischemia (Mann-Whitney U test). ^*p≤0.05, ^**p≤0.0001.