Impaired Balance of Mitochondria Fission and Fusion in Alzheimer Disease

By Xinglong Wang, B. Su, Hyoung-Gon Lee, Xinyi Li, George Perry, Mark A. Smith, Xiongwei Zhu. Journal of Neuroscience, 2009

1,145 citations recorded by the source corpus.

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-β-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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e8e9c940a86cc2002cd3abc8bb32bf0a8dd7c07a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. P. Reddy
2. J. Nunnari

In Molecular Biology

1. M. Calkins
2. M. Mańczak
3. A. Suomalainen
4. P. Reddy
5. Orian Shirihai
6. Xiongwei Zhu
7. Xinglong Wang
8. Wen Chen

In Physiology

1. M. Calkins
2. M. Mańczak
3. P. Reddy
4. Orian Shirihai
5. Xiongwei Zhu
6. A. Suomalainen
7. J. Nunnari
8. G. Twig

Citations in the corpus

• Synaptic energy use and supply. (2012, neutral): “Increased mitochondrial fission and decreased fusion occur, correlating with loss of dendritic spines (Wang et al., 2009), in part as a result of nitric oxide produced in response to the amyloid b (Ab) that is a hallmark of AD (Cho et al., 2009).”
• Mitochondrial dynamics in health and disease: mechanisms and potential targets (2023, background): “In addition, Opa1, Drp1, MFN1/2 expression are significantly lower in AD, whereas Fis1 levels are higher in AD.(185) Mitochondrial dynamics impact the pathological changes of AD involved in several signaling pathways, including Ca, AMPK, and nitric oxide signaling pathways.”
• Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease (2012, background): “In fact, both mitochondrial fission and fusion processes were impaired in ADDL-treated primary neurons [90].”
• Mitochondria: In Sickness and in Health (2012, background): “In cell culture models for neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, mitochondria typically fragment in response to the expression of misfolded proteins (Cho et al., 2010; Costa et al., 2010; Lutz et al., 20”
• The Interplay Between Mitochondrial Dynamics and Mitophagy (2011, background): “In an animal model of Alzheimer disease (116, 117) and a culture model of Parkinson disease (17), mitochondrial architecture was fragmented and the relative mitochondrial mass in APs was shown to be selectively increased (71).”
• Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. (2011, background): “(32,33), who also reported increased Fis1 in AD patients, although the progression of AD in their patients was not specified.”
• Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model (2010, background): “These findings are in agreement with those of recent studies indicating that Aβ causes rapid and severe impairment of mitochondrial transport (54) and alters mitochondrial dynamics (53).”
• Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “Soluble Aβ oligomers disrupted the balance between mitochondrial fission and fusion, leading to significant mitochondrial dysfunction.(197,198) Excessive mitocondrial fission is a key modulator of Aβ toxicity.”
• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Aβ-exposure also leads to the enrichment of proteins associated with increased mitochondrial fission and decreased mitochondrial fusion [96, 97].”
• Therapeutics of Alzheimer's disease: Past, present and future. (2014, background): “namics with altered levels of fission and fusion proteins also occurs with AD pathology (Wang et al., 2009); hence an agent that pre-”