WNT5A Signaling Contributes to Aβ-Induced Neuroinflammation and Neurotoxicity

Abstract

Neurodegenration is a pathological hallmark of Alzheimer's disease (AD), but the underlying molecular mechanism remains elusive. Here, we present evidence that reveals a crucial role of Wnt5a signaling in this process. We showed that Wnt5a and its receptor Frizzled-5 (Fz5) were up-regulated in the AD mouse brain, and that beta-amyloid peptide (Aβ), a major constituent of amyloid plaques, stimulated Wnt5a and Fz5 expression in primary cortical cultures; these observations indicate that Wnt5a signaling could be aberrantly activated during AD pathogenesis. In support of such a possibility, we observed that inhibition of Wnt5a signaling attenuated while activation of Wnt5a signaling enhanced Aβ-evoked neurotoxicity, suggesting a role of Wnt5a signaling in AD-related neurodegeneration. Furthermore, we also demonstrated that Aβ-induced neurotoxicity depends on inflammatory processes, and that activation of Wnt5a signaling elicited the expression of proinflammatory cytokines IL-1β and TNF-α whereas inhibition of Wnt5a signaling attenuated the Aβ-induced expression of the cytokines in cortical cultures. Our findings collectively suggest that aberrantly up-regulated Wnt5a signaling is a crucial pathological step that contributes to AD-related neurodegeneration by regulating neuroinflammation.

Wingless-type Mammary Tumor Virus Integration Site Family, Member 5A (Wnt5a) Regulates Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Glycoprotein 120 (gp120)-induced Expression of Pro-Inflammatory Cytokines via the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and c-Jun N-terminal Kinase (JNK) Signaling Pathways

“…Emerging evidence reveals a role of Wnt5a in regulation of peripheral inflammatory response (32-34, 36, 61). More recently, we showed that Wnt5a is critical for A␤-induced cytokine expression in cortical cultures (41). These prior findings suggest an interesting possibility that the gp120-induced up-regulation of Wnt5a is an early molecular event leading to gp120-elicited neuroinflammation.…”

“…Mouse Neuron Culture and Transfection-Primary cultures of cortical neurons were prepared as previously described (41). Briefly, the neurons was cultured in 12-well plates coated with poly-D-lysine containing Neurobasal medium supplemented with 10% B27 and 0.5 mM L-glutamine for 10 -14 days before use.…”

“…Cord-Our recent work uncovered a critical role of Wnt5a in regulation of cytokine expression in cortical neuron/glia-mixed cultures (41). In this study, we aimed to test the potential role of Wnt5a in regulating gp120-induced cytokine expression in the CNS.…”

Hyperphosphorylation of Tau Protein in Down ’s Dementia and Alzheimer’s Disease: Methylation and Implications in Prevention and Therapy

“…Further analysis of changes induced by SMF to date, seems to be particularly potent at modulating WNT5a as well as interleukin 6 (IL-6) via the toll-like receptor 4. Bei Li has published that aberrantly up-regulated Wnt5a signaling is a crucial pathological step that contributes to AD-related neurodegeneration by regulating neuroinflammation [61].…”

“…They found that GSK3beta and protein phosphatase 2 A (PP2A) were up-regulated by inhibiting methylation reactions through B vitamin deficiency. They concluded that one-carbon metabolism alteration seems to be the cause of deregulation of the equilibrium between GSKbeta and PP2A leading to abnormal hyperphosphorylated tau [61].…”