Genetic inhibition of PDK1 robustly reduces plaque deposition and ameliorates gliosis in the 5×FAD mouse model of Alzheimer's disease

Aims Abundant recent evidence has shown that 3‐phosphoinositide‐dependent protein kinase 1 (PDK1) is activated in Alzheimer's disease (AD). However, it remains unknown whether inhibition of PDK1 in neurons may affect AD‐like pathology in animal models of AD. Here, we aim to examine the effects...

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Published in:Neuropathology and applied neurobiology 2022-12, Vol.48 (7), p.e12839-n/a
Main Authors: Ye, Xiaolian, Chen, Lu, Wang, He, Peng, Shixiao, Liu, Mengjia, Yao, Liyang, Zhang, Yizhi, Shi, Yun Stone, Cao, Ying, Yang, Jian‐Jun, Chen, Guiquan
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animal models
APP
Forebrain
Gliosis
Inflammation
Kinases
memory deficit
Molecular modelling
Neurodegenerative diseases
neuroinflammation
Pathology
PDK1
Protein kinase
Rapamycin
S6K
Short term memory
Spatial memory
TOR protein
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Summary:Aims Abundant recent evidence has shown that 3‐phosphoinositide‐dependent protein kinase 1 (PDK1) is activated in Alzheimer's disease (AD). However, it remains unknown whether inhibition of PDK1 in neurons may affect AD‐like pathology in animal models of AD. Here, we aim to examine the effects of specific inactivation of neuronal PDK1 on pathology and behaviour in 5×FAD mice and to identify the underlying molecular mechanisms. Methods The Cre‐loxP system was employed to generate Pdk1 cKO/5×FAD mice, in which PDK1 is inactivated in excitatory neurons in the adult forebrain. Cellular and behavioural techniques were used to examine plaque burden, inflammatory responses and spatial working memory in mice. Biochemical and molecular analyses were conducted to investigate relevant mechanisms. Results First, Aβ deposition was massively decreased and gliosis was highly attenuated in Pdk1 cKO/5×FAD mice compared with 5×FAD mice. Second, memory deficits were significantly improved in Pdk1 cKO/5×FAD mice. Third, APP levels were notably decreased in Pdk1 cKO/5×FAD mice. Fourth, mammalian target of rapamycin (mTOR) signalling and ribosome biogenesis were reduced in Pdk1 cKO/5×FAD mice. Conclusions Neuron‐specific deletion of PDK1 robustly ameliorates AD‐like pathology and improves spatial working memory in 5×FAD mice. We propose that genetic approach to inhibit PDK1 may be an effective strategy to slow AD. In this study, we report that forebrain neuron‐specific deletion of PDK1 significantly reduces amyloid plaques and ameliorates gliosis in 5×FAD mice. We demonstrate that deletion of PDK1 inhibits APP expression via an mTOR‐dependent regulation of ribosome biogenesis. Our findings suggest that inhibition of PDK1 by genetic approaches may be a potential treatment strategy to halt the progression of AD.
ISSN:0305-1846
1365-2990
DOI:10.1111/nan.12839