Abstract
It is widely believed that one of the causes of Alzheimer's disease (AD) is the generation and secretion of beta-amyloid (Abeta) from amyloid precursor protein in the brain. Here we report that a transcription factor, NF-kappaB/p65, induces increased secretion of amyloidogenic Abeta42 but not Abeta40. The kappaB motif-dependent production of Abeta42 was suppressed by binding of NF-kappaB/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-kappaB/p65 to induce expression of protein(s) involved in Abeta42 production. The amino acids 161-163 in Rel homology domain (RHD) of NF-kappaB/p65 is important in interaction of NF-kappaB/p65 with X11L. Another subunit NF-kappaB/p50 and heterodimers of p65 and p50 do not bind to X11L. Our finding indicates NF-kappaB and X11L may, in novel way, regulate Abeta production in neuronal cells. Targeting X11L by specific therapy may provide the possibility to control the progression of AD.
Highlights
It is widely believed that one of the causes of Alzheimer’s disease (AD) is the generation and secretion of -amyloid (A) from amyloid precursor protein in the brain
While the mechanisms regulating the proteolytic cleavage of APP and secretion of A are as yet not well understood, we and others recently reported that X11 [6, 7] and X11-like protein (X11L) [2] proteins regulate APP metabolism and/or A production
NF-B/p65 was detected in the sample immunoprecipitated with two of the anti-hX11L antibodies UT-29 and UT-50, but detection with the third, UT-30, was weak because UT-30 competes with NF-B for the recognition sequence
Summary
It is widely believed that one of the causes of Alzheimer’s disease (AD) is the generation and secretion of -amyloid (A) from amyloid precursor protein in the brain. The results suggest that the PDZ domain of X11L can control the ability of NF-B/p65 to induce expression of protein(s) involved in A42 production. To determine whether the RHD participated in the binding of NF-B/p65 to hX11L, we performed another co-immunoprecipitation experiment using COS7 cells co-expressing hX11L and the RHD tagged with a FLAG sequence at their amino-terminal ends (Fig. 1d).
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