PDZ domain-dependent suppression of NF-κB/p65-induced Aβ42 production by a neuron-specific X11-like protein

Abstract

It is widely believed that one of the causes of Alzheimer's disease (AD) is the generation and secretion of β-amyloid (Aβ) from amyloid precursor protein in the brain. Here we report that a transcription factor, NF-κB/p65, induces increased secretion of amyloidogenic Aβ42 but not Aβ40. The κB motif-dependent production of Aβ42 was suppressed by binding of NF-κB/p65 to the PDZ domain of the X11-like protein (X11L), which a human homologue protein of LIN-10. The results suggest that the PDZ domain of X11L can control the ability of NF-κB/p65 to induce expression of protein(s) involved in Aβ42 production. The amino acids 161-163 in Rel homology domain (RHD) of NF-κB/p65 is important in interaction of NF-κB/p65 with X11L. Another subunit NF-κB/p50 and heterodimers of p65 and p50 do not bind to X11L. Our finding indicates NF-κB and X11L may, in novel way, regulate Aβ production in neuronal cells. Targeting X11L by specific therapy may provide the possibility to control the progression of AD.