Abstract
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 β- and γ-secretase activities in relation to amyloid-β (Aβ) pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-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 Aβ plaques, γ-secretase activity was significantly increased (∼1.6-fold) when compared to iNPH samples without Aβ plaques (p = 0.009). In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, β-secretase activity was unaltered in iNPH samples with or without Aβ plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not β-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aβ pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.
Highlights
The normal pressure hydrocephalus (NPH), which typically presents symptoms including deteriorated gait, impaired cognition and urinary incontinence with enlarged ventricles and normal or slightly elevated cerebrospinal fluid (CSF) pressure is a potentially dementing condition [1,2]
Before assessing the secretase activities according to the Ab pathology, we wanted to validate whether the visually detected Ab plaque counts correlated with more quantitative measures, such as soluble Ab x-42 (Ab42) levels and relative immunohistochemical Ab staining, in the sample set
Both soluble Ab42 levels and relative Ab staining revealed a significant difference between Ab2negative and Ab2positive idiopathic normal pressure hydrocephalus (iNPH) sample groups, validating the sample grouping based on the visual Ab plaque counts
Summary
The normal pressure hydrocephalus (NPH), which typically presents symptoms including deteriorated gait, impaired cognition and urinary incontinence with enlarged ventricles and normal or slightly elevated cerebrospinal fluid (CSF) pressure is a potentially dementing condition [1,2]. We set our goal to investigate whether alterations in b- and c-secretase activities in relation to Ab pathology are observed in the biopsy samples obtained from the frontal cortex of the iNPH patients.
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