Hebp1, or Heme-binding protein 1, is a mitochondrial-associated protein. It participates in heme metabolism, binds to heme, and modulates mitochondrial dynamics crucial for maintaining neural circuitry [1]. It is also associated with the AGE/RAGE-related neuronal damage pathway and is involved in the Nrf2-Keap1 signaling-related stress response pathway, which is a key intracellular defense mechanism against oxidative stress [2,3].

In Alzheimer's disease (AD), Hebp1 has emerged as an important mediator of neuronal cell death during early AD pathogenesis. Acting downstream of Aβ and heme, HEBP1-mediated apoptosis contributes to neuronal loss and neuronal circuit dysfunction. Deleting HEBP1 expression in neurons protects them from heme-and Aβ-induced apoptosis, both of which are mechanisms implicated in neurodegeneration [1]. In a mouse model of cavernous nerve injury, exogenously delivered Hebp1 improved erectile function by promoting the survival of cavernous endothelial-mural cells and neurons, and endogenous Hebp1 delivered by mouse cavernous pericyte-derived extracellular vesicles promoted neurovascular regeneration. Hebp1 achieved these effects by reducing vascular permeability through regulation of claudin family proteins [4].

In conclusion, Hebp1 is essential for maintaining neural and neurovascular functions. Gene-deletion models in neurons and in vivo mouse models of cavernous nerve injury have revealed its role in neurodegenerative diseases like AD and in peripheral nerve injury repair. Understanding Hebp1's functions provides insights into the mechanisms of these disease processes and potential therapeutic strategies [1,4].

References:

1. Chua, John Jia En. 2022. HEBP1 - An early trigger for neuronal cell death and circuit dysfunction in Alzheimer's disease. In Seminars in cell & developmental biology, 139, 102-110. doi:10.1016/j.semcdb.2022.07.005. https://pubmed.ncbi.nlm.nih.gov/35842370/

2. Bellezza, Ilaria, Giambanco, Ileana, Minelli, Alba, Donato, Rosario. 2018. Nrf2-Keap1 signaling in oxidative and reductive stress. In Biochimica et biophysica acta. Molecular cell research, 1865, 721-733. doi:10.1016/j.bbamcr.2018.02.010. https://pubmed.ncbi.nlm.nih.gov/29499228/

3. Baird, Liam, Yamamoto, Masayuki. 2020. The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway. In Molecular and cellular biology, 40, . doi:10.1128/MCB.00099-20. https://pubmed.ncbi.nlm.nih.gov/32284348/

4. Ock, Jiyeon, Wu, Jitao, Liu, Fang-Yuan, Jin, Hai-Rong, Ryu, Ji-Kan. 2023. Heme-binding protein 1 delivered via pericyte-derived extracellular vesicles improves neurovascular regeneration in a mouse model of cavernous nerve injury. In International journal of biological sciences, 19, 2663-2677. doi:10.7150/ijbs.81809. https://pubmed.ncbi.nlm.nih.gov/37324943/