Role of RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease

Rlip+/− mice show cognitive impairments, increased oxidative stress, and mitochondrial abnormalities, features similar to late-onset AD.

“Recently, we reported that mice with a heterozygous loss of Rlip (Rlip+/−) showed cognitive impairments, increased oxidative stress, and mitochondrial abnormalities, features similar to those seen in late-onset AD [14].”

Glutathione peroxidase activity decreased in Rlip+/− mice, indicating loss of mitochondrial function.

“Consistently, the activity of glutathione peroxidase, a mitochondrial antioxidant enzyme, decreased in the Rlip+/− mice, which also indicates a loss of mitochondrial function [14].”

Rlip+/− mice have significant increases in dentate gyrus and hippocampus expression of Drp1 and Fis1, and decreased expression of MFN1.

“Our recent findings show that heterozygous Rlip KO (Rlip+/−) mice have significant increases in the dentate gyrus and hippocampus expression of Drp1 and Fis1, genes involved with mitochondrial fission, and decreased expression of the mitofusin MFN1 [14].”

Rlip+/− mice have significant reductions of synaptophysin and PSD95 in brains relative to WT, likely indicating poor synaptic health.

“We recently examined the synaptic proteins synaptophysin and PSD95 and found significant reductions of both proteins in the brains of Rlip+/− mice relative to WT mice, likely indicating poor synaptic health [14].”

In brains of Rlip+/− mice, increased expression of NRF2 was found.

“Consistent with elevated ROS, in the brains of Rlip+/− mice we found increased expression of NRF2 [14], a master transcription factor which is activated by oxidative stress and which subsequently induces the cell’s antioxidant system.”

Electron microscopy images of hippocampal and cortical cells in Rlip+/− mice showed a larger number of smaller mitochondria relative to controls, indicating mitochondrial fragmentation.

“Electron microscopy images of hippocampal and cortical cells in Rlip+/− mice showed a larger number of smaller mitochondrial relative to controls with wild-type Rlip, indicating mitochondrial fragmentation [14].”

Gene network analysis indicated dysregulated expression of stress-activated genes, mitochondrial function genes, and CREB signaling genes in Rlip+/− mouse brain.

“Gene network analysis indicated dysregulated expression of stress-activated genes, mitochondrial function genes, and CREB signaling genes in the Rlip+/− mouse brain.”

Molecular markers of synaptic function, mitochondrial fission, fusion, and biogenesis are affected in brain tissues of Rlip+/− mice.

“Molecular markers of synaptic function, as well as mitochondrial fission, fusion, and biogenesis, were also affected in brain tissues obtained from these mice [14].”

Several lines of evidence support a key role for Rlip in detoxification of 4-HNE and response to oxidative stress.

“Several lines of evidence support a key role for Rlip in the detoxification of 4-HNE and response to oxidative stress [14,64,65], and thus the downregulation or degradation of Rlip may increase the damage caused by the elevated ROS emission resulting from amyloid β and mitochondrial dysfunction.”

Transmission electron microscopy of cortical and hippocampal tissues revealed abnormalities in both size and number of mitochondria in Rlip+/− mice.

“Transmission electron microscopy studies of cortical and hippocampal tissues revealed abnormalities in both the size and number of mitochondria.”

Halving Rlip gene dose by heterozygous knockout is sufficient to induce behavioral alterations and markers of oxidative stress and mitochondrial dysfunction in the brain.

“Significantly, these findings also show that a halving of Rlip gene dose by heterozygous Rlip knockout (KO) is sufficient to induce behavioral alterations and markers of oxidative stress and mitochondrial dysfunction in the brain.”