Dysregulation of Autophagy, Mitophagy, and Apoptosis Genes in the CA3 Region of the Hippocampus in the Ischemic Model of Alzheimer’s Disease in the Rat

Abstract

There is currently no knowledge about the expression profile of the autophagy (BECN1), mitophagy (BNIP3), and apoptosis (CASP3) genes in the CA3 region of the hippocampus after cerebral ischemia. In addition, it is unknown whether genes for BECN1, BNIP3, and CASP3 have any effect on the neuronal death in the CA3 area of the hippocampus due to ischemia. In this study, for the first time, we present, by means of a quantitative PCR protocol with reverse transcriptase, the expression of BECN1 and CASP3 genes in the neuronal CA3 region of the hippocampus with the co-expression of the mitochondrial BNIP3 gene, which genes are associated with Alzheimer's disease, in the ischemic model of Alzheimer's disease in the rat. The present study showed that after ischemia, the CASP3 gene was significantly expressed within 7-30 days, the BECN1 gene was significantly overexpressed on the thirtieth day, and the BINP3 gene was lowered below control values during post-ischemic follow-up period. The caspase-dependent neuronal death in the CA3 region of the hippocampus after ischemia is not accompanied by overexpression of the BNIP3 gene. Our data may therefore suggest a new insight into the BNIP3 gene in the regulation of neuronal mitophagy in neurodegeneration in the CA3 region of the hippocampus after ischemia. This indicates no involvement of the BNIP3 gene along with the CASP3 gene in the CA3 region of the hippocampus in delayed neuronal death after brain ischemia.

Participation of Amyloid and Tau Protein in Neuronal Death and Neurodegeneration after Brain Ischemia

“…Apoptosis has been noted in neurons of the CA1 region of the hippocampus 4 days after brain ischemia with reperfusion. Postischemia, caspase-3 plays a key role in the death of neurons [ 91 , 92 , 93 , 94 ]. The connection of autophagy and mitophagy with apoptosis should be suggested, too [ 91 , 92 , 93 , 94 ].…”

“…In this event, autophagosomes and autolysosomes are found in dying neuronal cells. Recent evidence indicated that autophagy and mitophagy play a significant role in postischemic brain injury [ 91 , 92 , 93 , 94 ].…”

Shared Genomic and Proteomic Contribution of Amyloid and Tau Protein Characteristic of Alzheimer’s Disease to Brain Ischemia

“…The increase in brain and serum amyloid levels [2,43,50,54,56] was associated with a similar increase in brain and blood levels of tau protein after ischemia [3,53,55,63], and these changes predict a worse clinical outcome. Ischemia-induced increase in tau protein gene expression was parallel to overexpression of caspase 3 gene and caspase plays an important role in neuronal death (Figure 3) [11,12,152]. The data showed that activated caspase positively correlates with the development of neurofibrillary tangles [3].…”

“…In addition, ultrastructural changes after ischemia were observed in hippocampus synapses [7][8][9]. Other studies have shown that an episode of cerebral ischemia leads to the induction of synaptic autophagy, which may be associated with loss of neurons in the hippocampus after transient cerebral ischemia [5][6][7][8][10][11][12]. Intracellular calcium increase post-ischemia [5] stimulates the activity of calpain in neurons whose target proteins are found in GABAergic and glutaminergic synapses [7].…”

Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms

“…Recent studies on the expression of these genes, at the mRNA level, in models of rats with ischemia or Alzheimer’s disease with ischemia [ 51 , 52 , 53 ] have also demonstrated great variability in the expression of these autophagic and mitophagic genes in CA1 [ 51 ] and CA3 [ 52 ] regions of the hippocampus, as well as in temporal lobe of the cerebral cortex [ 53 ]. In the latter, marked differences were reported between the expression of Becn1 and BNIP 3 after a temporal course of 30 days after ischemia—that of Becn1 being high at the beginning, with a tendency to decrease during the 30 days of the reperfusion period, and that of BNIP3 having a tendency to ascend in the mid-term and then to decrease.…”