p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer's disease.
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
X-Q
XQ
Yao
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
S-S
SS
Jiao
Neuroregeneration Laboratory, School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
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K
Saadipour
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
F
F
Zeng
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
Q-H
QH
Wang
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
C
C
Zhu
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
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LL
Shen
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
G-H
GH
Zeng
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
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CR
Liang
Neuroregeneration Laboratory, School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
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http://orcid.org/0000-0002-6227-6112
J
Wang
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
Y-H
YH
Liu
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
H-Y
HY
Hou
First Department, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
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X
Xu
Institute of Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
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YP
Su
Third Military Medical University, Chongqing, China.
X-T
XT
Fan
Department of Pathology, Daping Hospital, Third Military Medical University, Chongqing, China.
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HL
Xiao
Laboratory of Neuroinflammation, Sun Health Research Institute, Sun City, AZ, USA.
L-F
LF
Lue
Key Laboratory of Stem Cells and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
Y-Q
YQ
Zeng
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
B
B
Giunta
Neuroregeneration Laboratory, School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
J-H
JH
Zhong
Laboratory of Neuroinflammation, Sun Health Research Institute, Sun City, AZ, USA.
D G
DG
Walker
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
H-D
HD
Zhou
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
J
J
Tan
Neuroregeneration Laboratory, School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.|Key Laboratory of Stem Cells and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
X-F
XF
Zhou
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
Y-J
YJ
Wang
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000209:etiology / Q000628:therapy; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000627:therapeutic use; D014161:Transduction, Genetic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; D051722:ADAM Proteins; D000072198:ADAM17 Protein