Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer's pathology in mice.
Neuropathol Appl Neurobiol
; 47(5): 611-624, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-33341972
ABSTRACT
AIMS:
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.METHODS:
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.RESULTS:
mKlk8-knockdown had negligible effects on wildtype animals but led to significant decline of amyloid beta (Aß) 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 Aß phagocytosis in primary glia and Aß resistance in primary neurons. Most importantly, transgenic mice revealed less anxiety and a better memory performance.CONCLUSIONS:
These results reinforce the potential of KLK8 as a therapeutic target in AD.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Calicreínas
/
Factores Sexuales
/
Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Neuropathol Appl Neurobiol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania