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.

Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia

“…These data corroborate earlier immunohistochemical observations from animal models of global brain ischemia and from brains after global brain ischemia in humans, which all suggest a direct relationship between ischemia and increased level of A␤ peptide accumulation in the brain tissue [19][20][21]. The findings presented above highlight a different and/or delayed regulatory mode in ischemia-induced cell death in temporal cortex as compared to hippocampus through an A␤ peptide-dependent manner [35,36]. These observations will help to understand the gradual postischemic damage in the brain, delayed A␤ peptide deposition and slow and long-term ischemic spreading neuropathology of AD from hippocampus into medial temporal lobe cortex and other parts of the brain [25,35,36,60,61].…”

“…The findings presented above highlight a different and/or delayed regulatory mode in ischemia-induced cell death in temporal cortex as compared to hippocampus through an A␤ peptide-dependent manner [35,36]. These observations will help to understand the gradual postischemic damage in the brain, delayed A␤ peptide deposition and slow and long-term ischemic spreading neuropathology of AD from hippocampus into medial temporal lobe cortex and other parts of the brain [25,35,36,60,61]. The present data may partly help to define the molecular mechanism of higher occurrence of neuronal death in ischemic layers 3, 5, and 6 of medial temporal lobe cortex.…”

“…The dysregulation of all studied genes at this time negatively correlates with intra-and extracellular immunostaining of the respective gene products [17,21,41,43]. Intra-and extracellular A␤ peptide immunoreactivity increases for as long as a year after injury [43], indicating that A␤ peptide accumulation may continue long after amyloid-␤ protein precursor metabolism processing gene expression drops to below normal value [17,35,53].…”

“…The most prevalent pathological hallmark of AD is the accumulation of plaques formed by A␤ peptide, commencing in the hippocampus, and spreading progressively throughout the brain [35,60,61]. It is likely that this accumulation in temporal cortex is caused by both increased inflow from blood [54,55] and impaired clearance of A␤ peptide [62].…”

“…Unfortunately, the relationship between hippocampus neuronal injury and medial temporal lobe injury in brain ischemia and AD has received little attention. On the basis of the known anatomical connectivity between the hippocampus and medial temporal lobe, we hypothesized that in ischemic brain injury of hippocampus there would be an association with neuronal pathology in temporal cortex as measured by regional related metabolism of amyloid-␤ protein precursor genes [35,36]. What is more, we intended to understand how A␤ peptide deposition induces ischemic remodeling in medial temporal lobe cortex.…”