Genetic knockdown of Klk8 has sex‐specific multi‐targeted therapeutic effects on Alzheimer’s pathology in mice

Abstract

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Is kallikrein-8 a blood biomarker for detecting amnestic mild cognitive impairment? Results of the population-based Heinz Nixdorf Recall study

“…Our lab was the first to demonstrate elevated cerebral KLK8 levels in the very early stages of AD disease, i.e., in AD patients with the onset of the first Aβ plaques and in transgenic mice even before the onset of Aβ pathology [ 19 ]. Moreover, several aspects of AD pathology could be alleviated by antibody-mediated inhibition of KLK8 [ 19 , 21 ] or the genetic knockdown of KLK8 in transgenic mice [ 22 ]. Interestingly, single nucleotide polymorphisms (SNPs) in KLK8 [ 50 ] similar to CD33 [ 51 ], TOMM40 [ 52 ], and APOE [ 53 ] are all located in the same chromosomal region 19q13 which apparently is strongly associated with AD risk.…”

“…This exceedingly early (in mice prior to onset of amyloid pathology; in patients in CERAD A/Braak I-II stage) and multifocal rise of KLK8 [ 19 ] is suggestive of a causal role in the cascade of events leading to AD. This hypothesis is supported further by the fact that even a short-term inhibition of this enzyme by an anti-KLK8-antibody [ 19 , 21 ] or its long-term downregulation by genetic knockdown [ 22 ], exerted considerable therapeutic effect in transgenic mice. It impedes amyloidogenic amyloid-precursor-protein processing, facilitates Aβ clearance, boostes autophagy, reduces Aβ load and tau pathology, enhances neuroplasticity, improves memory, and unfolds anxiolytic effects [ 19 , 21 , 22 ].…”

“…This hypothesis is supported further by the fact that even a short-term inhibition of this enzyme by an anti-KLK8-antibody [ 19 , 21 ] or its long-term downregulation by genetic knockdown [ 22 ], exerted considerable therapeutic effect in transgenic mice. It impedes amyloidogenic amyloid-precursor-protein processing, facilitates Aβ clearance, boostes autophagy, reduces Aβ load and tau pathology, enhances neuroplasticity, improves memory, and unfolds anxiolytic effects [ 19 , 21 , 22 ]. Furthermore, KLK8 levels were also elevated in blood and CSF of patients with MCI due to AD and early AD [ 23 ].…”

Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1

“…Antidepressants are found to alter the expression of KLK8 in the hippocampus [35]. Several studies have suggested the critical role of KLK8 in the pathogenesis of anxiety-related behaviors due to different etiologies [21,[36][37][38]. However, to the best of our knowledge, only one study reported that the severity of depression-like behaviors induced by chronic stress or chronic corticosterone injection is reduced in KLK8-de cient mice [31].…”

“…An important implication of hippocampal KLK8 upregulation contributing to CUMS-induced depressionlike behavior is that KLK8-targeted therapy may have clinical relevance for patients with depression. In fact, increased levels of KLK8 have been implicated in the pathogenesis of various brain diseases including schizophrenia, mood and anxiety disorders, autoimmune encephalomyelitis and Alzheimer's disease [17,[37][38][39]. The critical role of KLK8 in this wide spectrum of diseases motivated the development of KLK8-targeted therapies such as macroglobulins, peptide-based and small molecule inhibitors and antibodies [39,40].…”