LRP1 and RAGE Genes Transporting Amyloid and Tau Protein in the Hippocampal CA3 Area in an Ischemic Model of Alzheimer’s Disease with 2-Year Survival

Abstract

Explaining changes at the gene level that occur during neurodegeneration in the CA3 area is crucial from the point of view of memory impairment and the development of post-ischemic dementia. An ischemic model of Alzheimer’s disease was used to evaluate changes in the expression of genes related to amyloid transport in the CA3 region of the hippocampus after 10 min of brain ischemia with survival of 2, 7 and 30 days and 12, 18 and 24 months. The quantitative reverse transcriptase PCR assay revealed that the expression of the LRP1 and RAGE genes involved in amyloid transport was dysregulated from 2 days to 24 months post-ischemia in the CA3 area of the hippocampus. LRP1 gene expression 2 and 7 days after ischemia was below control values. However, its expression from day 30 to 24 months, survival after an ischemic episode was above control values. RAGE gene expression 2 days after ischemia was below control values, reaching a maximum increase 7 and 30 days post-ischemia. Then, after 12, 18 and 24 months, it was again below the control values. The data indicate that in the CA3 area of the hippocampus, an episode of brain ischemia causes the increased expression of the RAGE gene for 7–30 days during the acute phase and that of LRP1 from 1 to 24 months after ischemia during the chronic stage. In other words, in the early post-ischemic stage, the expression of the gene that transport amyloid to the brain increases (7–30 days). Conversely, in the late post-ischemic stage, amyloid scavenging/cleaning gene activity increases, reducing and/or preventing further neuronal damage or facilitating the healing of damaged sites. This is how the new phenomenon of pyramidal neuronal damage in the CA3 area after ischemia is defined. In summary, post-ischemic modification of the LRP1 and RAGE genes is useful in the study of the ischemic pathways and molecular factors involved in the development of Alzheimer’s disease.

Trans- and Cis-Phosphorylated Tau Protein: New Pieces of the Puzzle in the Development of Neurofibrillary Tangles in Post-Ischemic Brain Neurodegeneration of the Alzheimer’s Disease-like Type

“…If the trend in ischemic brain injury continues, by 2030 approximately 12 million cases will die, 70 million will survive ischemia, and each year there will be disability for over 200 million years [ 4 , 6 ]. Based on the latest clinical and experimental evidence, it was hypothesized that an episode of brain ischemia may contribute to the development of Alzheimer’s disease [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Growing evidence shows that brain ischemia causes neurodegeneration of the Alzheimer’s disease-like phenotype and genotype, and provides new insight into the similar mechanisms of changes that may be involved in the development of both diseases, but the ultimate answer underlying their co-development remains unknown [ 17 , 18 , 21 ].…”

“…It has been shown that vasoconstriction during recirculation [ 27 ] is accompanied by the development of cerebral amyloid angiopathy [ 2 ], also observed in Alzheimer’s disease. During recirculation, oxidative stress affects the genome, causing DNA damage, neuronal, glial and endothelial cell death, and neurological outcomes [ 17 , 18 , 25 , 28 ]. In post-ischemic neurodegeneration, acetylcholine loss was mainly found in the hippocampus [ 29 ], similar to the brain in Alzheimer’s disease.…”

“…While changes in gene expression in the temporal cortex immediately occurred post ischemia and did not occur throughout survival and did not involve all genes ( Table 1 ) [ 36 , 37 ]. The data revealed that post-ischemic brain injury in animals and humans induced amyloidogenic processes in the examined brain structures [ 9 , 18 , 25 , 38 , 39 ].…”