HEBP1 - An early trigger for neuronal cell death and circuit dysfunction in Alzheimer's disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that gradually impairs memory, cognition and the ability to perform simple daily tasks. It is the most prevalent form of dementia in the elderly and its incidence increases exponentially with age. Neuronal and synapse loss, key hallmarks of the disorder, are widely regarded to occur early during the onset of AD, and the extent of this loss closely correlates with the progression of cognitive decline and dysfunction of the underlying neuronal circuity. Nevertheless, the mechanisms driving neuronal and synapse loss during early AD remains poorly understood. This review focuses on Heme-binding protein 1 (HEBP1), a mitochondrial-associated protein that has recently 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. HEBP1 participates in heme metabolism and binds to heme to modulate mitochondrial dynamics vital to the maintenance of neural circuitry that is affected in AD. HEBP1 elevation is also associated with AGE/RAGE-related neuronal damage, further implicating its involvement in neuronal loss during early AD. Moreover, F2L, a cleavage product of HEBP1 modulates inflammation. Collectively, these findings highlight the importance of HEBP1 in the disruption of neural circuits during early AD.