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.

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Native hyaluronan (HAn) is poor in exerting anti‐inflammatory responses. However, interchain‐dissociated or conformationally altered HA significantly inhibits complement activation. To induce interchain dissociation, HA was heat treated, quickly frozen, and quickly thawed prior to interacting with serum complement. Here, HAn is subjected to sonication for indicated times. Heat was generated up to 70oC during sonication. Time‐related sonication HA preparations (HAson) exhibit various extent of degradation. These samples are conformationally altered due to heat treatment for 1 to 24 hr and the resulting degradation. We examined whether HAn and HAson block rotenone‐induced Parkinson’s disease (PD) in mice. Rotenone, an environmental pesticide, inhibits mitochondrial complex I and causes aggregation of α‐synuclein for leading to neuronal death. Immune competent BALB/c and C57BL/6 mice received PBS, HAn, or HAson preparations (200 μg in 100 µl PBS) via tail vein injections for two consecutive weeks, and were allowed to rest for 14 days. The mice were then challenged with rotenone (5 mg/kg) via subcutaneous injections and subjected to indicated tests two weeks later. Mice receiving HAson8 (sonication for 8 hours) significantly resisted the development of rotenone‐induced acute PD symptoms (~80% of improved mouse mobility by footprint analysis), as compared to mice receiving PBS, HAn, and other HAson preparations (4, 12, 16 and 24 hr sonication), respectively. HAson8 also blocked pentylenetetrazol‐mediated seizure in mice. All the HA preparations were not toxic to the animals, and did not alter the normal behavior of mice during experiments involving rotarod test and Barnes water maze analysis. As a potent inhibitor of Alzheimer’s disease, Zfra4‐10 peptide significantly restores memory loss, reduces PTZ‐mediated seizure and retards PD progression. Mechanistically, Zfra4‐10 binds membrane hyaluronidase Hyal‐2 to signal with WWOX and Smad4 to activate Hyal‐2+ spleen Z cells for blocking neurodegeneration. It is suggested that compared to HAn, HAson8 strongly binds membrane Hyal‐2 for Z cell activation and mitigating PD symptoms.