Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/ JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the lowdensity lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a À499A4G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the À499A4G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the þ 766C4T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A4G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

Confocal microscopy of entorhinal cortex tissue of Alzheimer's type, double-labelled with anti-IB1/JIP1 and antiphosphorylated Tau (picture taken with TCS NT of Leica). IB1/JIP-1 colocalizes with phosphorylated Tau proteins in neurofibrillary tangles. For more information on this topic, please see the article by Helbecque et al on pages 413-422 of this issue.