Decreased Cerebrospinal Fluid Levels of Neurosin (KLK6), an Aging‐Related Protease, as a Possible New Risk Factor for Alzheimer's Disease

Abstract

Neurosin is a kallikrein-like serine protease expressed preferentially in the human brain. It is localized in senile plaques and neurofibrillary tangles in the brains of individuals with Alzheimer's disease (AD) and in Lewy bodies in patients with Parkinson's disease. Neurosin is present in the cerebrospinal fluid (CSF) as a proenzyme and does not show any enzymatic activity. We have developed a sandwich ELISA system using monoclonal and polyclonal antibodies against human neurosin and have measured neurosin levels in the CSF from AD and non-CNS disease patients. Both male and female patients with peripheral neuropathy showed statistically positive correlations between CSF neurosin concentrations and age (males, n = 52, r = 0.482, p < 0.005; females, n = 43, r = 0.365, p < 0.005). In contrast, such positive correlation was not observed in the CSF from patients with AD. Further, some such patients showed extremely low levels of CSF neurosin. Our results suggest that neurosin is an aging-related protease and that a decreased CSF concentration of neurosin may be a risk factor for developing AD.

Substrate Specificity of Human Kallikrein 6

“…Given the dense expression of hK6 by oligodendroglia of the normal CNS (35,36), these data further suggest that hK6 is likely to play a physiologic role in normal myelin turnover. The brain of Alzheimer disease patients was described to contain significantly less hK6 than the brain of nonaffected individuals (39,40). hK6 was also observed in cerebrospinal fluid; however, the amount of hK6 in this biological compartment is controversial in Alzheimer disease patients, because it was described by Mitsui et al (40) to be decreased and by Diamandis et al (41) to be increased.…”

“…hK6 was demonstrated to play an important role in the progression of inflammatory diseases of the CNS and in its demyelination processes (37,38). hK6 is reduced in brain extracts of Alzheimer disease patients (39,40) and increased in serum of patients with ovarian cancer (41,42). hK6 exists mainly as a proenzyme in milk and cerebrospinal fluid, and a fraction of hK6 was described to be partially complexed with ␣ 1 -antichymotrypsin in milk and ascites fluid of ovarian cancer patients (43).…”

Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

“…Some of these kallikreins are found at relatively high levels in CSF. A few studies have already associated AD with levels kallikreins in either brain tissues or CSF [15,16,[19][20][21][22]. It was thus logical to hypothesize that the concentration of certain kallikrein enzymes in CSF may be associated with neurodegeneration.…”

“…Kallikrein gene (KLK) 6 mRNA has been demonstrated in many brain regions and in spinal cord [17], and hK6 enzyme has been immunohistochemically localized in choroid plexus epithelium, Purkinje cells, and glial cells [18]. Mitsui et al [19] speculated that this kallikrein is related to aging and is a new risk factor for Alzheimer's disease and that its CSF concentration is reduced in some patients with Alzheimer's disease. Previously, Little et al [20] have shown that this protease may have amyloidogenic potential.…”

Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier

“…Among the KLKs expressed in the central nervous system (CNS), KLK6 has been implicated in multiple sclerosis (Scarisbrick et al, 2002;Blaber et al, 2004), Alzheimer's disease (Little et al, 1997;Diamandis et al, 2000;Ogawa et al, 2000;Mitsui et al, 2002;Zarghooni et al, 2002), and Parkinson's disease (Ogawa et al, 2000;Iwata et al, 2003). Furthermore, KLK8 (also known as brain serine peptidase or neuropsin) may play a role in synaptic plasticity (Shimizu et al, 1998;Yousef et al, 2003), long-term potentiation (Tamura et al, 2006), and neurodegeneration (Terayama et al, 2007).…”