The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus

被引：10

作者：

Shen, Chen ^{[1
,2
]}

Chen, Cong ^{[1
,2
]}

Wang, Tong ^{[1
,2
]}

Gao, Tong-Yao ^{[1
,2
]}

Zeng, Min ^{[1
,2
]}

Lu, Yun-Bi ^{[1
,2
]}

Zhang, Wei-Ping ^{[1
,2
]}

机构：

[1] Zhejiang Univ, Sch Med, Dept Pharmacol, Hangzhou 310058, Zhejiang, Peoples R China

[2] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Neurosurg, Hangzhou 310009, Zhejiang, Peoples R China

来源：

MOLECULAR NEUROBIOLOGY | 2023年 / 60卷 / 03期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

NAMPT (nicotinamide phosphoribosyltransferase); NAD (nicotinamide adenine dinucleotide); Mitochondria homeostasis; Neurodegeneration; IN-VIVO; NAD(+); NEURODEGENERATION; DYSFUNCTION; EXPRESSION; DELETION; STRESS; MODEL; MICE;

D O I：

10.1007/s12035-022-03142-5

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the salvaging synthesis pathway of the nicotinamide adenine dinucleotide (NAD). Both NAMPT and NAD progressively decline upon aging and neurodegenerative diseases. The depletion of NAMPT induces mitochondrial dysfunction in motor neurons and causes bioenergetic stress in neurons. However, the roles of NAMPT in hippocampus neurons need to be further studied. Using floxed Nampt (Nampt(flox/flox)) mice, we knocked out Nampt specifically in the hippocampus CA1 neurons by injecting rAAV-hSyn-Cre-APRE-pA. The depletion of NAMPT in hippocampus neurons induced cognitive deficiency in mice. Nevertheless, no morphological change of hippocampus neurons was observed with immunofluorescent imaging. Under the transmission electron microscope, we observed mitochondrial swollen and mitochondrial number decreasing in the cell body and the neurites of hippocampus neurons. In addition, we found the intracellular A beta (6E10) increased in the hippocampus CA1 region. The intensity of A beta 42 remained unchanged, but it tended to aggregate. The GFAP level, an astrocyte marker, and the Iba1 level, a microglia marker, significantly increased in the mouse hippocampus. In the primary cultured rat neurons, NAMPT inhibition by FK866 decreased the NAD level of neurons at > 10(-9) M. FK866 dropped the mitochondrial membrane potential in the cell body of neurons at > 10(-9) M and in the dendrite of neurons at > 10(-8) M. FK866 decreased the number and shortened the length of branches of neurons at > 10(-7) M. Together, likely due to the injury of mitochondria, the decline of NAMPT level can be a critical risk factor for neurodegeneration.

引用

页码：1267 / 1280

页数：14