Higher levels of kallikrein‐8 in female brain may increase the risk for Alzheimer's disease

Abstract

Women seem to have a higher vulnerability to Alzheimer's disease (AD), but the underlying mechanisms of this sex dichotomy are not well understood. Here, we first determined the influence of sex on various aspects of Alzheimer's pathology in transgenic CRND8 mice. We demonstrate that beta-amyloid (Aβ) plaque burden starts to be more severe around P180 (moderate disease stage) in female transgenics when compared to males and that aging aggravates this sex-specific difference. Furthermore, we show that female transgenics suffer from higher levels of neurovascular dysfunction around P180, resulting in impaired Aβ peptide clearance across the blood-brain-barrier at P360. Female transgenics show also higher levels of diffuse microgliosis and inflammation, but the density of microglial cells surrounding Aβ plaques is less in females. In line with this finding, testosterone compared to estradiol was able to improve microglial viability and Aβ clearance in vitro. The spatial memory of transgenics was in general poorer than in wildtypes and at P360 worse in females irrespective of their genotype. This difference was accompanied by a slightly diminished dendritic complexity in females. While all the above-named sex-differences emerged after the onset of Aβ pathology, kallikrein-8 (KLK8) protease levels were, as an exception, higher in female than in male brains very early when virtually no plaques were detectable. In a second step, we quantified cerebral KLK8 levels in AD patients and healthy controls, and could ascertain, similar to mice, higher KLK8 levels not only in AD-affected but also in healthy brains of women. Accordingly, we could demonstrate that estradiol but not testosterone induces KLK8 synthesis in neuronal and microglial cells. In conclusion, multiple features of AD are more pronounced in females. Here, we show for the first time that this sex-specific difference may be meditated by estrogen-induced KLK8 overproduction long before AD pathology emerges.

CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer’s disease

“…As recently shown28 KLK8 levels seem to be higher in AD affected and non-affected female murine and human brain when compared with male individuals, while contrastingly no correlations were found between CSF or blood KLK8 levels and gender in this work. No significant correlations were also detectable between CSF or blood KLK8 values and APOE genotype.…”

A is for Autophagy and Alzheimer's

“…A higher level of KLK8 is detected in brains of female Alzheimer's disease patients at early disease stages compared with male counterparts. These studies conclude by suggesting that KLK8 overexpression and accompanying impaired autophagy in females is central to the preferential prevalence of AD in females [75].…”

“…As described earlier, the significant sexspecific differences in AD are related to estrogen-induced overproduction of KLK8 in prodromal AD. KLK8 is manifest in AD affected areas: the hippocampus, frontal cortex and cerebellum [75]. Inhibition of KLK8 enhances autophagy and, in animal models, reduces amyloid and tau pathology [120].…”

Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-β accumulation in Alzheimer’s disease

“…EXOC2 (exocyst complex component 2) was reported for nominal association with AD age of onset modifier genes through a whole-exome study (Velez et al 2016 ). For KLK8 (kallikrein-related peptidase 8), it was previously shown that its mRNA levels in AD hippocampus were significantly higher than in controls (Shimizu-Okabe et al 2001 ), and its protease was recently reported as a suggestive factor for increasing the risk for AD specifically in females (Keyvani et al 2018 ). ATXN1 (ataxin 1) was screened for one of the candidates associated with AD through a GWAS and functionally validated its loss of function of increased Aβ-protein levels by potentiating beta-secretase processing of beta-amyloid precursor protein (Zhang et al 2010 ).…”