The interaction between AbetaPP and JIP1 as a mechanism for linking transcriptional activation and the JNK stress pathway to Alzheimer's disease pathogenesis

Abstract

Alzheimer's disease (AD) is characterized clinically as a progressive unremitting dementia and pathologically by amyloid-beta (Abeta) plaques, neurofibrillary tangles, and neurodegeneration in the brain. AD has always been a serious problem due to the devastating effects on the individual but is now becoming an even greater public health problem as people are living longer due to improvements in general health. A major belief in the field is that accumulation of the Abeta peptide which is derived from the transmembrane region of amyloid beta protein precursor (AbetaPP) is the primary event in AD pathology. Recent data though has suggested that another peptide, the AbetaPP intracellular domain (AID), may also contribute substantially to the pathology seen in the disease. In order to understand the role of AID, we identified JNK Interacting Protein (JIP) 1, a scaffold protein in the JNK signaling cascade, to bind AID. We further found that the two other AbetaPP family members, amyloid precursor like protein (APLP) 1 and 2, also produce AID-like fragments. Using two different systems we found that JIP1 can cause transcriptional activation along with AbetaPP but not the APLPs, and that JIP1 can facilitate JNK dependent AbetaPP phosphorylation but not phosphorylation of the APLPs. Considering that AbetaPP but not the APLPs are genetically linked to AD, and that JIP1 acts only with AbetaPP, JIP1 may underlie the asymmetric roles of the AbetaPP family members seen in AD. JIP1 which functions in the JNK signaling cascade which mediates the cell's apoptosis and survival pathways may represent a biochemical link between AD and the cell death seen in the brains of these patients. Understanding more fully the link between AD molecules and the cell's death and survival pathways will allow a more complete understanding of AD and new avenues for prevention and treatment.