Low-Density Lipoprotein Receptor-Related Protein 1 as a Potential Therapeutic Target in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid ß (Aß) plagues in the brain is the main pathological hallmark of AD. The Aß deposits are formed due to the imbalance between the production and Aß clearance in the brain and across the blood-brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays a significant role by mediating both brain Aß production and clearance. Due to its important role in AD pathogenesis, LRP1 is considered an attractive drug target for AD therapies. In the present review, we summarize the current knowledge about the role of LRP1 in AD pathogenesis as well as recent findings on changes in LRP1 expression and function in AD. Finally, we discuss the advances in utilizing LRP1 as a drug target for AD treatments as well as future perspectives on LRP1 research.

Increased Expression of Transferrin Receptor 1 in the Brain Cortex of 5xFAD Mouse Model of Alzheimer's Disease Is Associated with Activation of HIF-1 Signaling Pathway.

Alzheimer's disease (AD) is the most common cause of dementia. Despite intensive research efforts, there are currently no effective treatments to cure and prevent AD. There is growing evidence that dysregulation of iron homeostasis may contribute to the pathogenesis of AD. Given the important role of the transferrin receptor 1 (TfR1) in regulating iron distribution in the brain, as well as in the drug delivery, we investigated its expression in the brain cortex and isolated brain microvessels from female 8-month-old 5xFAD mice mimicking advanced stage of AD. Moreover, we explored the association between the TfR1 expression and the activation of the HIF-1 signaling pathway, as well as oxidative stress and inflammation in 5xFAD mice. Finally, we studied the impact of Aß1-40 and Aß1-42 on TfR1 expression in the brain endothelial cell line hCMEC/D3. In the present study, we revealed that an increase in TfR1 protein levels observed in the brain cortex of 5xFAD mice was associated with activation of the HIF-1 signaling pathway as well as accompanied by oxidative stress and inflammation. Interestingly, incubation of Aß peptides in hCMEC/D3 cells did not affect the expression of TfR1, which supported our findings of unaltered TfR1 expression in the isolated brain microvessels in 5xFAD mice. In conclusion, the study provides important information about the expression of TfR1 in the 5xFAD mouse model and the potential role of HIF-1 signaling pathway in the regulation of TfR1 in AD, which could represent a promising strategy for the development of therapies for AD.