Role of WWOX/WOX1 in Alzheimer's disease pathology and in cell death signaling

Alzheimer's disease (AD) is the most common form of dementia with a progressive course. AD pathology is a manifestation of the underlying severity and neuroanatomic involvement of specific vulnerable brain regions and circuits that are responsible for neuronal dysfunction and death. The etiology of AD is largely unknown. It has been hypothesized that multiple factors, including genetic components, oxidative stress, intracellular or extracellular accumulation of amyloid, dysfunction of cystoskeletal and synapse components, neuronal loss by apoptosis, neuronal excitotoxicity, inflammation, mitochondria dysfunction, etc., may play important roles in the onset of the disease. WWOX/WOX1 is a candidate tumor suppressor. Human WWOX gene, encoding the WW domain-containing oxidoreductase (designated WWOX, FOR, or WOX1) protein, has been mapped to a fragile site on the chromosome ch16q23.3-24.1. Functionally, the WW domain is not only a tumor suppressor, but also a participant in molecular interactions, signaling, and apoptosis in many diseases. In this article, we review the potential mechanism by which WWOX/WOX1 may participate in the pathogenesis of AD with a focus on cell death signaling pathways in neurons.