Impaired balance of mitochondrial fission and fusion in Alzheimer's disease.
Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-beta-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.
Wang
Xinglong
X
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Su
Bo
B
Lee
Hyoung-gon
HG
Li
Xinyi
X
Perry
George
G
Smith
Mark A
MA
Zhu
Xiongwei
X
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001710:Biotin / Q000378:metabolism; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D034281:Dynamins; D004622:Embryo, Mammalian; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D016253:Microscopy, Immunoelectron / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000648:ultrastructure*; D011180:Postmortem Changes; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; C476525:FIS1 protein, human; C489787:MAP2 protein, rat; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C085348:tau-1 monoclonal antibody; D049452:Green Fluorescent Proteins; D001710:Biotin; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C415198:OPA1 protein, human; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins