Abstract
WW domain-containing oxidoreductase (WWOX) is known as one of the risk factors for Alzheimer’s disease (AD), a neurodegenerative disease. WWOX binds Tau via its C-terminal SDR domain and interacts with Tau phosphorylating enzymes ERK, JNK, and GSK-3β, and thereby limits AD progression. Loss of WWOX in newborns leads to severe neural diseases and early death. Gradual loss of WWOX protein in the hippocampus and cortex starting from middle age may slowly induce aggregation of a protein cascade that ultimately causes accumulation of extracellular amyloid beta plaques and intracellular tau tangles, along with reduction in inhibitory GABAergic interneurons, in AD patients over 70 years old. Age-related increases in pS14-WWOX accumulation in the brain promotes neuronal degeneration. Suppression of Ser14 phosphorylation by a small peptide Zfra leads to enhanced protein degradation, reduction in NF-κB-mediated inflammation, and restoration of memory loss in triple transgenic mice for AD. Intriguingly, tumor suppressors p53 and WWOX may counteract each other in vivo, which leads to upregulation of AD-related protein aggregation in the brain and lung. WWOX has numerous binding proteins. We reported that the stronger the binding between WWOX and its partners, the better the suppression of cancer growth and reduction in inflammation. In this regard, the stronger complex formation between WWOX and partners may provide a better blockade of AD progression. In this review, we describe whether and how WWOX and partner proteins control inflammatory response and protein aggregation and thereby limit AD progression.
Highlights
It appears that hyperphosphorylated tau protein captured in the extracellular vesicles (EV) is conformationally altered and is pathogenic
Tau undergoes misfolding during the period from middle to old age, and the misfolded proteins are transmitted among neurons prior to the appearance of Alzheimer’s disease (AD) symptoms
WWOX deficiency in newborns suffer the disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), early infantile epileptic encephalopathy (EIEE), and WWOX-related epileptic encephalopathy (WOREE syndrome) [60,61,62,63,69,70,71,72,73]
Summary
Alzheimer’s disease (AD) is the most common cause (60–75%) of dementia and an age-related neurodegenerative disease. For early-onset AD, the symptoms may start in patients in their 30s or 40s due to gene mutations inherited in an autosomal dominant fashion [1,2,3]. Gene mutations of amyloid precursor protein (APP) on chromosome 21, presenilin 1 (PSEN1) on chromosome 14, and presenilin 2 (PSEN2) on chromosome 1 are associated with early-onset AD [1,2,3]. Protein aggregates are present in the brains of healthy middle-aged individuals, suggesting that AD progression may start gradually in middle-aged humans [4,5,6,7]. Aggregate formation of tau and Aβ levels in the brains are very low in middle-aged healthy humans of 40 to 70 years old [4,5,6,7]. Aβ and tau aggregates are able to invoke neuronal death and block neurogenesis and learning and memory capabilities in old AD patients
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