Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer's pathology in mice.
Alzheimer’s disease
KLK8
TgCRND8 mouse
genetic knockdown
kallikrein-8
neuroplasticity
neuropsin
therapeutic target
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
23
11
2020
received:
05
08
2020
accepted:
14
12
2020
pubmed:
21
12
2020
medline:
1
2
2022
entrez:
20
12
2020
Statut:
ppublish
Résumé
Previous work in our lab has identified the protease kallikrein-8 (KLK8) as a potential upstream mover in the pathogenesis of Alzheimer's disease (AD). We showed pathologically elevated levels of KLK8 in the cerebrospinal fluid and blood of patients with mild cognitive impairment or dementia due to AD, and in brains of patients and transgenic CRND8 (TgCRND8) mice in incipient stages of the disease. Furthermore, short-term antibody-mediated KLK8 inhibition in moderate stage disease alleviated AD pathology in female mice. However, it remains to be shown whether long-term reversal of KLK8 overexpression can also counteract AD. Therefore, the effects of genetic Klk8-knockdown were determined in TgCRND8 mice. The effects of heterozygous ablation of murine Klk8 (mKlk8) gene on AD pathology of both sexes were examined by crossbreeding TgCRND8 [hAPP+/-] with mKlk8-knockdown [mKlk8+/-] mice resulting in animals with or without AD pathology which revealed pathologically elevated or normal KLK8 levels. mKlk8-knockdown had negligible effects on wildtype animals but led to significant decline of amyloid beta (Aβ) and tau pathology as well as an improvement of structural neuroplasticity in a sex-specific manner in transgenics. These changes were mediated by a shift to non-amyloidogenic cleavage of the human amyloid precursor protein (APP), recovery of the neurovascular unit and maintaining microglial metabolic fitness. Mechanistically, Klk8-knockdown improved Aβ phagocytosis in primary glia and Aβ resistance in primary neurons. Most importantly, transgenic mice revealed less anxiety and a better memory performance. These results reinforce the potential of KLK8 as a therapeutic target in AD.
Substances chimiques
Amyloid beta-Peptides
0
Amyloid beta-Protein Precursor
0
Kallikreins
EC 3.4.21.-
Prss19 protein, mouse
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
611-624Informations de copyright
© 2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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