Endoplasmic Reticulum Stress-inducible Protein, Herp, Enhances Presenilin-mediated Generation of Amyloid β-Protein* 210

Presenilin (PS) is essential for the γ-cleavage required for the generation of the C terminus of amyloid β-protein (Aβ). However, the mechanism underlying PS-mediated γ-cleavage remains unclear. We have identified Herp cDNA by our newly developed screening method for the isolation of cDNAs that increase the degree of γ-cleavage. Herp was originally identified as a homocysteine-responsive protein, and its expression is up-regulated by endoplasmic reticulum stress. Herp is an endoplasmic reticulum-localized membrane protein that has a ubiquitin-like domain. Here, we report that a high expression of Herp in cells increases the level of Aβ generation, although not in PS-deficient cells. We found that Herp interacts with both PS1 and PS2. Thus, Herp regulates PS-mediated Aβ generation, possibly through its binding to PS. Immunohistochemical analysis of a normal human brain section with an anti-Herp antibody revealed the exclusive staining of neurons and vascular smooth muscle cells. Moreover, the antibody strongly stained activated microglia in senile plaques in the brain of patients with Alzheimer disease. Taken together, Herp could be involved in Aβ accumulation, including the formation of senile plaques and vascular Aβ deposits.