Increased γ-Secretase Activity in Idiopathic Normal Pressure Hydrocephalus Patients with β-Amyloid Pathology

The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated beta- and gamma-secretase activities in relation to amyloid-beta (A beta) pathology in the brain tissue samples collected from iNPH and AD patients. beta- and gamma-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable A beta plaques, gamma-secretase activity was significantly increased (similar to 1.6-fold) when compared to iNPH samples without A beta plaques (p=0.009). In the AD samples, statistically significant differences in the gamma-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, beta-secretase activity was unaltered in iNPH samples with or without A beta plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased gamma-secretase but not b-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like A beta pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the A beta pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of A beta.