PMID- 35881686
OWN - NLM
STAT- MEDLINE
DCOM- 20221104
LR  - 20221104
IS  - 1365-2990 (Electronic)
IS  - 0305-1846 (Linking)
VI  - 48
IP  - 7
DP  - 2022 Dec
TI  - Genetic inhibition of PDK1 robustly reduces plaque deposition and ameliorates 
      gliosis in the 5xFAD mouse model of Alzheimer's disease.
PG  - e12839
LID - 10.1111/nan.12839 [doi]
AB  - 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 5xFAD mice and to 
      identify the underlying molecular mechanisms. METHODS: The Cre-loxP system was 
      employed to generate Pdk1 cKO/5xFAD 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, Abeta deposition was massively decreased and 
      gliosis was highly attenuated in Pdk1 cKO/5xFAD mice compared with 5xFAD mice. 
      Second, memory deficits were significantly improved in Pdk1 cKO/5xFAD mice. 
      Third, APP levels were notably decreased in Pdk1 cKO/5xFAD mice. Fourth, 
      mammalian target of rapamycin (mTOR) signalling and ribosome biogenesis were 
      reduced in Pdk1 cKO/5xFAD mice. CONCLUSIONS: Neuron-specific deletion of PDK1 
      robustly ameliorates AD-like pathology and improves spatial working memory in 
      5xFAD mice. We propose that genetic approach to inhibit PDK1 may be an effective 
      strategy to slow AD.
CI  - (c) 2022 British Neuropathological Society.
FAU - Ye, Xiaolian
AU  - Ye X
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Chen, Lu
AU  - Chen L
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Wang, He
AU  - Wang H
AD  - Department of Anesthesiology, Pain and Perioperative Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
FAU - Peng, Shixiao
AU  - Peng S
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Liu, Mengjia
AU  - Liu M
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Yao, Liyang
AU  - Yao L
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Zhang, Yizhi
AU  - Zhang Y
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Shi, Yun Stone
AU  - Shi YS
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Cao, Ying
AU  - Cao Y
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
FAU - Yang, Jian-Jun
AU  - Yang JJ
AD  - Department of Anesthesiology, Pain and Perioperative Medicine, The First 
      Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
FAU - Chen, Guiquan
AU  - Chen G
AUID- ORCID: 0000-0002-4674-5548
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing 
      University, Nanjing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220731
PL  - England
TA  - Neuropathol Appl Neurobiol
JT  - Neuropathology and applied neurobiology
JID - 7609829
RN  - 146-14-5 (Flavin-Adenine Dinucleotide)
RN  - 0 (Pdk1 protein, mouse)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Alzheimer Disease/pathology
MH  - Disease Models, Animal
MH  - Flavin-Adenine Dinucleotide
MH  - Gliosis
MH  - Mice, Transgenic
MH  - Plaque, Amyloid/pathology
MH  - *Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics
OTO - NOTNLM
OT  - APP
OT  - Alzheimer's disease
OT  - PDK1
OT  - S6K
OT  - memory deficit
OT  - neuroinflammation
EDAT- 2022/07/27 06:00
MHDA- 2022/11/04 06:00
CRDT- 2022/07/26 13:53
PHST- 2022/05/05 00:00 [revised]
PHST- 2021/10/25 00:00 [received]
PHST- 2022/07/04 00:00 [accepted]
PHST- 2022/07/27 06:00 [pubmed]
PHST- 2022/11/04 06:00 [medline]
PHST- 2022/07/26 13:53 [entrez]
AID - 10.1111/nan.12839 [doi]
PST - ppublish
SO  - Neuropathol Appl Neurobiol. 2022 Dec;48(7):e12839. doi: 10.1111/nan.12839. Epub 
      2022 Jul 31.