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Mitochondrial alterations in Alzheimer's disease.
Literature Information
| DOI | 10.3233/jad-2006-9204 |
|---|---|
| PMID | 16873959 |
| Journal | Journal of Alzheimer's disease : JAD |
| Impact Factor | 3.1 |
| JCR Quartile | Q2 |
| Publication Year | 2006 |
| Times Cited | 148 |
| Keywords | Mitochondrial alterations, Alzheimer's disease, Metabolic defects, Neuronal toxicity, Oxidative stress |
| Literature Type | Journal Article, Review |
| ISSN | 1387-2877 |
| Pages | 119-26 |
| Issue | 9(2) |
| Authors | Stavros J Baloyannis |
TL;DR
This study investigates the morphological and morphometric changes of mitochondria in neurons from various brain regions affected by Alzheimer's disease, revealing significant alterations such as reduced size and changes in cristae structure, alongside a correlation with synaptic damage and loss of dendritic spines. These findings highlight the critical role of mitochondrial dysfunction in the pathophysiology of Alzheimer's disease, suggesting that mitochondrial alterations may serve as early indicators of neuronal degeneration and provide insights for potential therapeutic targets.
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Mitochondrial alterations · Alzheimer's disease · Metabolic defects · Neuronal toxicity · Oxidative stress
Abstract
Morphological alterations of mitochondria may be related to metabolic and energy deficiency in neurons in Alzheimer's disease and other neurodegenerative disorders. Mitochondrial dysfunction is also a hallmark of beta peptide induced neuronal toxicity in Alzheimer's disease. A general change in glucose utilization, increased oxidative stress, and Ca;{2+} deregulation are additional metabolic defects in the AD brain that may also be associated with defective mitochondrial function the result is a cycle of increased mitochondrial dysfunction causing increased oxidative damage until the cellular energy supply falls below the threshold for cellular survival. In a series of studies on the morphological and morphometric estimation of mitochondria in Alzheimer's disease, by electron microscopy we noticed substantial morphological and morphometric changes in the neurons of the hippocampus, the acoustic cortex, the frontal cortex, the cerebellar cortex, the climbing fibers, the thalamus, the globus pallidus, the red nucleus and the locus coeruleus. The morphological alterations consisted of considerable changes of the mitochondrial cristae, accumulation of osmiophilic material, and decrease of their size, in comparison with the normal controls. Mitochondrial alterations were particularly prominent in neurons, which showed loss of dendritic spines and abbreviation of the dendritic arborization. The ultrastructural study of large number of neurons in the thalamus and the red nucleus revealed that the mitochondrial alterations did not coexist with cytoskeletal pathology and accumulation of amyloid deposits, though they were prominent in neurons, which demonstrated fragmentation of the cisternae of the Golgi apparatus. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship between the site and extent of mitochondrial abnormalities and the synaptic alterations suggests an intimate and early association between these features in Alzheimer's disease.
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Primary Questions Addressed
- What specific morphological changes in mitochondria have been observed in different regions of the brain affected by Alzheimer's disease?
- How do mitochondrial dysfunctions contribute to the metabolic defects observed in neurons of Alzheimer's patients?
- In what ways could targeting mitochondrial health potentially serve as a therapeutic approach for Alzheimer's disease?
- What role does oxidative stress play in the relationship between mitochondrial alterations and neuronal toxicity in Alzheimer's disease?
- How do the findings on mitochondrial changes in Alzheimer's disease compare to those in other neurodegenerative disorders?
Key Findings
Research Background and Objectives
Alzheimer's disease (AD) is characterized by neurodegenerative processes that lead to cognitive decline and memory impairment. A significant aspect of this pathology involves mitochondrial alterations, which are believed to contribute to metabolic and energy deficiencies in neurons. The primary objective of this research is to explore the morphological and functional changes in mitochondria within various neuronal populations affected by Alzheimer's disease, with a particular focus on understanding how these changes relate to neuronal toxicity induced by beta peptides and other metabolic dysfunctions.
Main Methods and Findings
The study employed electron microscopy to conduct a detailed morphometric analysis of mitochondria in neurons from multiple brain regions, including the hippocampus, acoustic cortex, frontal cortex, cerebellar cortex, thalamus, and others. Key findings revealed substantial morphological changes in AD-affected neurons, including alterations in mitochondrial cristae structure, accumulation of osmiophilic material, and a significant reduction in mitochondrial size compared to controls. These mitochondrial abnormalities were linked to a loss of dendritic spines and a reduction in dendritic arborization, indicating that mitochondrial dysfunction may contribute to synaptic deficits in AD. Notably, the study found that while mitochondrial alterations were prominent, they did not coexist with cytoskeletal pathology or amyloid deposits in certain neuronal populations, suggesting a distinct pathological process.
Core Conclusions
The research concludes that mitochondrial alterations in neurons are an early and significant feature of Alzheimer's disease. The observed morphological changes are closely associated with synaptic impairments, highlighting a potential causal relationship between mitochondrial dysfunction and the neurodegenerative processes characteristic of AD. Furthermore, the findings emphasize that mitochondrial dysfunction precedes and potentially exacerbates oxidative stress and metabolic dysregulation in the AD brain.
Research Significance and Impact
This study provides critical insights into the role of mitochondrial dysfunction in the pathophysiology of Alzheimer's disease. By elucidating the specific morphological changes in mitochondria and their implications for neuronal health and synaptic integrity, the research underscores the importance of targeting mitochondrial function in therapeutic strategies for AD. The identification of early mitochondrial alterations as a hallmark of the disease could pave the way for novel diagnostic tools and interventions aimed at mitigating neurodegeneration and improving patient outcomes in Alzheimer's disease. Overall, this work contributes to a deeper understanding of the complex interplay between mitochondrial health, neuronal integrity, and the progression of neurodegenerative disorders.
Literatures Citing This Work
- Redox reactions of copper complexes formed with different beta-amyloid peptides and their neuropathological [correction of neuropathalogical] relevance. - Dianlu Jiang;Lijie Men;Jianxiu Wang;Yi Zhang;Sara Chickenyen;Yinsheng Wang;Feimeng Zhou - Biochemistry (2007)
- Novel genetic tools reveal Cdk5's major role in Golgi fragmentation in Alzheimer's disease. - Kai-Hui Sun;Yolanda de Pablo;Fabien Vincent;Emmanuel O Johnson;Angela K Chavers;Kavita Shah - Molecular biology of the cell (2008)
- Amyloid, hyperactivity, and metabolism: theoretical comment on Vloeberghs et al. (2008). - Dave Morgan;Marcia N Gordon - Behavioral neuroscience (2008)
- Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. - Gilad Twig;Brigham Hyde;Orian S Shirihai - Biochimica et biophysica acta (2008)
- Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. - Xinglong Wang;Bo Su;Sandra L Siedlak;Paula I Moreira;Hisashi Fujioka;Yang Wang;Gemma Casadesus;Xiongwei Zhu - Proceedings of the National Academy of Sciences of the United States of America (2008)
- Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. - Fulvio Celsi;Paola Pizzo;Marisa Brini;Sara Leo;Carmen Fotino;Paolo Pinton;Rosario Rizzuto - Biochimica et biophysica acta (2009)
- S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. - Dong-Hyung Cho;Tomohiro Nakamura;Jianguo Fang;Piotr Cieplak;Adam Godzik;Zezong Gu;Stuart A Lipton - Science (New York, N.Y.) (2009)
- The Alzheimer's disease mitochondrial cascade hypothesis: an update. - Russell H Swerdlow;Shaharyar M Khan - Experimental neurology (2009)
- Protective effects of compound FLZ, a novel synthetic analogue of squamosamide, on beta-amyloid-induced rat brain mitochondrial dysfunction in vitro. - Fang Fang;Geng-tao Liu - Acta pharmacologica Sinica (2009)
- Amyloid precursor protein transgenic mouse models and Alzheimer's disease: understanding the paradigms, limitations, and contributions. - Tyler A Kokjohn;Alex E Roher - Alzheimer's & dementia : the journal of the Alzheimer's Association (2009)
... (138 more literatures)
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