Genistein protects against amyloid‐beta‐induced toxicity in SH‐SY5Y cells by regulation of Akt and Tau phosphorylation

Abstract

Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of amyloid‐β (Aβ) peptide and hyperphosphorylation of Tau protein, which ultimately leads to the formation of intracellular neurofibrillary tangles and cell death. Increasing evidence indicates that genistein, a soy isoflavone, has neuroprotective effects against Aβ‐induced toxicity. However, the molecular mechanisms involved in its neuroprotection are not well understood. In this study, we have established a neuronal damage model using retinoic‐acid differentiated SH‐SY5Y cells treated with different concentrations of Aβ25–35 to investigate the effect of genistein against Aβ‐induced cell death and the possible involvement of protein kinase B (PKB, also termed Akt), glycogen synthase kinase 3β (GSK‐3β), and Tau as an underlying mechanism to this neuroprotection. Differentiated SH‐SY5Y cells were pre‐treated for 24 hr with genistein (1 and 10 nM) and exposed to Aβ25–35 (25 μM), and we found that genistein partially inhibited Aβ induced cell death, primarily apoptosis. Furthermore, the protective effect of genistein was associated with the inhibition of Aβ‐induced Akt inactivation and Tau hyperphosphorylation. These findings reinforce the neuroprotective effects of genistein against Aβ toxicity and provide evidence that its mechanism may involve regulation of Akt and Tau proteins.

Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

“…A recent study reported that the tyrosine kinase inhibitor sunitinib downregulates the tau kinase CDK5 and tau phosphorylation in gp120 Tg mice [40]. In addition, genistein modulates Aβ-induced tau phosphorylation in SH-SY5Y cells [35]. In the present study, we found that regorafenib injection selectively regulated tau phosphorylation in 5x FAD mice by decreasing the activity of the tau kinase GSK3β (Figure 8).…”

“…The AD brain is marked by two neuropathological characteristics-Aβ accumulation and tau tangle formation. Several studies have shown an association between tyrosine kinase inhibitors and AD pathology [20,35]. For instance, in Aβ-treated human cells or rat brain cortical cultures, tyrosine phosphorylation of numerous neuronal proteins is increased, including tau, and this tyrosine phosphorylation is inhibited by treatment with the tyrosine kinase inhibitor PP2 [36].…”

Genistein alleviates chronic vascular inflammatory response via the miR‑21/NF‑κB p65 axis in lipopolysaccharide‑treated mice

“…GEN is the major natural isoflavone in soy and soy-based foods (49) and can inhibit inflammation (50), delay aging (51) and prevent senile dementia (52); however, the underlying mechanisms are yet to be fully elucidated. As a potent pro-inflammatory cytokine, TNF-α participates in early vascular inflammation by upregulating aortic chemokines and adhesion molecules (53).…”

The Potential Effects of Phytoestrogens: The Role in Neuroprotection

“…The results suggested that genistein protects cells against Aβ-induced cytotoxicity, probably by regulating the expression of apoptosis-related proteins and Ca 2+ influx through ionotropic glutamate receptors [ 51 ]. According to more recent evidence, the protective effect of genistein is associated with the inhibition of Aβ-induced Akt inactivation and Tau hyperphosphorylation [ 52 ].…”