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Mol Neurodegener. 2018 Feb 1;13(1):5. doi: 10.1186/s13024-018-0238-8.

Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex.

Author information

1
Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, USA.
2
Department of Neurology, the second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
3
School of Pharmaceutical Engineering & Life Sciences, Changzhou University, Changzhou, Jiangsu, 213164, China.
4
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5
Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, OH, 44106, USA.
6
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14222, USA.
7
Department of Biology, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA.
8
Department of Neurology & Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. jly0520@hotmail.com.
9
Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, USA. xiongwei.zhu@case.edu.

Abstract

BACKGROUND:

Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer Disease (AD). It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. Mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelles. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the neurological disease.

METHODS:

To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout neuronal Mfn2 in the hippocampus and cortex, areas significantly affected in AD.

RESULTS:

Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the Mfn2 cKO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while in the cortex, progressive neuronal death was associated with decreased cortical size.

CONCLUSIONS:

Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many of the neurodegenerative changes and eventual neuron loss that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD.

PMID:
29391029
PMCID:
PMC5796581
DOI:
10.1186/s13024-018-0238-8
[Indexed for MEDLINE]
Free PMC Article

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