Wnt signaling pathway overcomes the disruption of neuronal differentiation of neural progenitor cells induced by oligomeric amyloid β-peptide

Neural stem cells give rise to new hippocampal neurons throughout adulthood. Defects in neurogenesis are associated with cognitive dysfunctions, such as Alzheimer disease (AD). Our understanding of the signals controlling this process is limited. The present in vitro study explored the manner in which the Wnt signaling pathway regulates the differentiation of hippocampal progenitors (HPs) into neurons under the influence of amyloid β₄₂ (Aβ₄₂). The results showed that oligomeric Aβ₄₂ reduced neuronal differentiation. This process was accompanied by a reduction in active β-catenin levels and proneural gene expression. The addition of Wnt3a increased the neuronal differentiation of Aβ₄₂-treated HPs, at the expense of astrocyte differentiation. The effect of Wnt signaling was attributable to progenitor cell differentiation to the neuronal lineage, and not to increased proliferation or rescue of neurons. The interruption of Wnt signaling by oligomeric Aβ₄₂ may have clinical implications for the treatment of impaired neurogenesis in AD.