Volume 9, Number 2, July 2006 - Special Issue "Mitochondria in Alzheimer's Disease" (Guest Editor: Paula I. Moreira and Catarina Oliveira)

Page 99
Paula I. Moreira and Catarina Oliveira
Foreword: Mitochondria in Alzheimer Disease

Pages 101-110
PI Moreira, SM Cardoso, MS Santos, CR Oliveira
The key role of mitochondria in Alzheimer's disease
Abstract: Mitochondria are uniquely poised to play a pivotal role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between amyloid-ß toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage/death in Alzheimer's disease pathophysiology. The knowledge that mitochondrial dysfunction has a preponderant role in Alzheimer's disease opened a window for new therapeutic strategies aimed to preserve/ameliorate mitochondrial function. Based on recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of ‘Mitochondrial Medicine' as a whole new field of biomedical research being this topic discussed in the last section of this review.

Pages 111-117
Michelangelo Mancuso, Gabriele Siciliano, Massimiliano Filosto, Luigi Murri
Mitochondrial dysfunction and Alzheimer's disease: new developments
Abstract: There is substantial evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with Alzheimer's disease (AD). However, the precise role of mitochondria in the neurodegenerative cascade leading to AD is still unclear, leaving the answer to the question “what's first: the chicken or the egg?” pending. Here we focus our attention on the progress made in this field in the past few years, which indicates a key role of this fossil organelle and of its specific DNA in contributing to the disease.

Pages 119-126
Stavros J. Baloyannis
Mitochondrial alterations in Alzheimer’s disease
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 Aß peptide induced neuronal toxicity in Alzheimer's disease. A general change in glucose utilization, increased oxidative stress, and Ca2+ 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.

Pages 127-137
Shi Du Yan, Wen-Cheng Xiong, David M. Stern
Mitochondrial Amyloid-Beta Peptide: pathogenesis or late-phase development?
Abstract: Mitochondrial and metabolic dysfunction have been linked to Alzheimer’s disease for some time. Key questions regarding this association concern the nature and mechanisms of mitochondrial dysfunction, and whether such changes in metabolic properties are pathogenic or secondary, with respect to neuronal degeneration. In terms of mitochondria and Alzheimer’s, altered function could reflect intrinsic properties of this organelle, potentially due to mutations in mitochondrial DNA, or extrinsic changes secondary to signal transduction mechanisms activated in the cytosol. This review presents data relevant to these questions, and considers the implication of recent findings demonstrating the presence of amyloid-ß peptide in mitochondria, as well as intra-mitochondrial molecular targets with which it can interact. Regardless of the underlying mechanism(s), it is likely that mitochondrial dysfunction contributes to oxidant stress which is commonly observed in brains of patients with Alzheimer’s and transgenic models of Alzheimer’s-like pathology.

Pages 139-146
Uta Keil, Susanne Hauptmann, Astrid Bonert, Isabel Scherping, Anne Eckert, Walter E. Müller
Mitochondrial dysfunction induced by disease relevant AßPP and tau protein mutations
Abstract: Alzheimer's disease is characterized by two major pathological hallmarks: extracellular plaques consisting of amyloid ß peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Mutations in the amyloid ß-protein precursor (AßPP) have been linked to familial Alzheimer's disease. They are leading to increased amyloid ß production. Mutations in the tau gene have not been described in AD, but are leading to formation of neurofibrillary tangles very similar to filaments in AD brains, and are therefore of increasing relevance in AD research. Interestingly, our data indicate that mutations in AßPP gene and mutations in tau gene induce mitochondrial dysfunction and oxidative stress in cell culture models and transgenic mice. Thus, both Alzheimer relevant protein alterations seem to have synergistic actions probably at the level of mitochondria leading to synaptic dysfunction and apoptotic cell death.

Pages 147-153
Xiongwei Zhu, George Perry, Paula I. Moreira, Gjumrakch Aliev, Adam D. Cash, Keisuke Hirai, Mark A. Smith
Mitochondrial Abnormalities and Oxidative Imbalance in Alzheimer Disease
Abstract: A number of mitochondrial and metabolic abnormalities were identified in the hippocampal neurons of Alzheimer disease compared to age-matched controls. Hippocampal neurons are the most vulnerable to disease associated pathology (i.e., cell death and proteinaceous lesions) and contain numerous markers of oxidative stress. Interestingly we found that the levels of mitochondrial DNA and cytochrome oxidase-1 in these neurons are markedly increased compared with those of age-matched control brains, even though the number of mitochondria per neuron is decreased. We hypothesize that the increased levels of mitochondrial DNA and cytochrome oxidase-1 may reflect an attempt by oxidatively-challenged neurons to replicate mitochondria, albeit unsuccessfully, as a response to the energetic/oxidative stress. Indeed, in this context, numerous signs of mitosis are observed in pyramidal neurons. Mitotic signals that promote cell cycle re-entry might be expected to also signal the synthesis of new mitochondria. Alternatively, these abnormalities may indicate altered turnover of mitochondrial components as a result of reduced degradation of mitochondrial byproducts or altered mitochondrial transport that redistributes mitochondrial DNA and cytochrome oxidase-1 to the cell body.

Pages 155-166
Shigeo Ohta and Ikuroh Ohsawa
Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer’s disease
Abstract: The mitochondrion is an organelle that plays a central role in energy production. It, at the same time, generates reactive oxygen species as by-products. Large-scale epidemiological case-control studies suggest the involvements of dihydrolipoamide succinyltransferase (DLST) of the mitochondrial Krebs cycle and mitochondrial aldehyde dehydrogenase-2 (ALDH2) in Alzheimer’s disease (AD). The DLST gene has two gene-products, one of which, a novel gene product MIRTD, mediates the molecular assembly of the cytochrome c oxidase complex whose defect has been a candidate of the causes of AD. Since levels of MIRTD mRNA in the brains of AD patients were significantly low, a decrease in MIRTD could affect energy production. ALDH2, a matrix enzyme, was found to act as a protector against oxidative stress through oxidizing toxic aldehydes, such as 4-hydroxy-2-nonenal, that are spontaneously produced from lipid peroxides. Hence, a decrease in ALDH2 activity is proposed to contribute to AD. Indeed, transgenic mice with low activity of ALDH2 exhibited an age-dependent neurodegeneration accompanying memory loss. Since amyloid ß peptide has been recently shown to be present in neuronal mitochondria to decline energy production and enhance ROS production, it has become possible to link AD more closely with roles of mitochondria in the pathogenesis.

Pages 167-181
Suzanne M. de la Monte, Jack R. Wands
Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease
Abstract: Glucose uptake and energy metabolism in the brain are regulated by insulin and insulin-like growth factors (IGF). Recent studies demonstrated progressive deficiencies in brain insulin and IGF production and responsiveness, and linked these abnormalities to acetylcholine deficiency in Alzheimer’s disease (AD). We extended this line of research by attempting to correlate the deficits in insulin/IGF signaling and energy production with mitochondrial dysfunction, oxidative injury, and compensatory cyto-protective responses in brains with different Braak Stage severities of AD. Real time quantitative RT-PCR analysis of frontal lobe tissue demonstrated significantly reduced expression of mitochondria-encoded Complex IV and V genes, with relative preservation of genes encoding Complexes I, II and III. In addition, AD was associated with significantly increased expression of the p53 pro-apoptosis gene, all 3 isoforms of nitric oxide synthase (NOS 1-3), and NADPH-oxidase (NOX) 1 and NOX 3, beginning early in the course of disease. Activation of cyto-protective mechanisms in AD brains was limited since the expression levels of uncoupling protein (UCP) 2, 4, and 5, and peroxisome-proliferator activated receptor (PPAR) alpha and delta genes were significantly reduced, whereas PPAR-gamma expression was selectively increased. The results demonstrate that AD is associated with early and striking increases in the molecular indices of oxidative stress, including up-regulation of NOS and NOX genes, which could impair the function of Complexes IV and V within the electron transport chain. The simultaneous reductions in cyto-protective mechanisms (UCP and PPAR), could allow oxidative injury to go unchecked and persist or increase over time. Adopting strategies to reduce the effects of NOS and NOX activities, and improve the actions of UCPs and PPARs may help in the treatment of AD.

Pages 195-205
David A.DeWitt, Jennifer A.Hurd, Nena Fox, Brigitte E.Townsend, Kathleen J.S.Griffioen, Othman Ghribi, John Savory
Peri-nuclear clustering of mitochondria is triggered during aluminum maltolate induced apoptosis
Abstract: Synapse loss and neuronal death are key features of Alzheimer's disease pathology. Disrupted axonal transport of mitochondria is a potential mechanism that could contribute to both. As the major producer of ATP in the cell, transport of mitochondria to the synapse is required for synapse maintenance. However, mitochondria also play an important role in the regulation of apoptosis. Investigation of aluminum (Al) maltolate induced apoptosis in human NT2 cells led us to explore the relationship between apoptosis related changes and the disruption of mitochondrial transport. Similar to that observed with tau over expression, NT2 cells exhibit peri-nuclear clustering of mitochondria following treatment with Al maltolate. Neuritic processes largely lacked mitochondria, except in axonal swellings. Similar, but more rapid results were observed following staurosporine administration, indicating that the clustering effect was not specific to Al maltolate. Organelle clustering and transport disruption preceded apoptosis. Incubation with the caspase inhibitor zVAD-FMK effectively blocked apoptosis, however failed to prevent organelle clustering. Thus, transport disruption is associated with the initiation, but not necessarily the completion of apoptosis. These results, together with observed transport defects and apoptosis related changes in Alzheimer disease brain suggest that mitochondrial transport disruption may play a significant role in synapse loss and thus the pathogenesis or Alzheimer’s disease.

Pages 207-218
John P. Blass, Gary E. Gibson
Correlations of disability and biologic alterations in Alzheimer brain and test of significance by a therapeutic trial in humans
Abstract: Literature values for the correlations between a number of major neurobiological hallmarks of Alzheimer's disease (AD) and the degree of global cognitive impairment among AD patients have been compared, in an attempt to identify biological abnormalities whose treatment might ameliorate the clinical disabilities. High correlations have been described with impairments of cerebral metabolism at both the level of cerebral metabolic rate in vivo and that of mitochondria. The metabolic abnormality develops even before morphological or symptomatic evidence of the illness. Information on such correlations with markers of oxidative stress are not available. Correlations with morphological abnormalities were lower and less consistent than with brain oxidative metabolism; significant correlations have been observed, in descending order, with a synaptic marker (synaptophysin), with tangle count, and with amyloid. Neither a decrease in a synaptic marker nor in a marker for cholinergic neurons have been found in mild, early AD. Preliminary therapeutic trials of manipulations designed to increase cerebral metabolic rate have given encouraging results, including a trial described briefly in this communication. The clinical value of treatments of the cerebrometabolic deficiency in AD warrants further investigation.

Pages 219-224
Transcript: Alzheimer Research Forum Live Discussion
Now You See Them, Now You Don't: The Amyloid Channel Hypothesis

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