Journal of Alzheimer's Disease - Volume 9, issue 2

Authors: Moreira, Paula I. | Oliveira, Catarina

Article Type: Editorial

DOI: 10.3233/JAD-2006-9201

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 99-99, 2006

Authors: Moreira, P.I. | Cardoso, S.M. | Santos, M.S. | Oliveira, C.R.

Article Type: Research Article

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-β 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. Show more

Keywords: Alzheimer's disease, amyloid β, mitochondria, oxidative stress, apoptosis

DOI: 10.3233/JAD-2006-9202

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 101-110, 2006

Authors: Mancuso, Michelangelo | Siciliano, Gabriele | Filosto, Massimiliano | Murri, Luigi

Article Type: Research Article

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.

Keywords: Mitochondria, mtDNA, neurodegeneration, Alzheimer's disease

DOI: 10.3233/JAD-2006-9203

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 111-117, 2006

Authors: Baloyannis, Stavros J.

Article Type: Research Article

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 β 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. Show more

Keywords: Alzheimer's disease, mitochondria, ultrastructure, morphometry, oxidative stress

DOI: 10.3233/JAD-2006-9204

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 119-126, 2006

Authors: Yan, Shi Du | Xiong, Wen-Cheng | Stern, David M.

Article Type: Research Article

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-β 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. Show more

Keywords: Respiratory chain complex, Alzheimer's disease, neurodegeneration, reactive oxygen species, apoptosis

DOI: 10.3233/JAD-2006-9205

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 127-137, 2006

Authors: Keil, Uta | Hauptmann, Susanne | Bonert, Astrid | Scherping, Isabel | Eckert, Anne | Müller, Walter E.

Article Type: Research Article

Abstract: Alzheimer's disease is characterized by two major pathological hallmarks: extracellular plaques consisting of amyloid β peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Mutations in the amyloid β-protein precursor (AβPP) have been linked to familial Alzheimer's disease. They are leading to increased amyloid β 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 AβPP 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. Show more

Keywords: Alzheimer's disease, mitochondria, amyloid β, oxidative stress, tau, amyloid β-protein precursor

DOI: 10.3233/JAD-2006-9206

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 139-146, 2006

Authors: Zhu, Xiongwei | Perry, George | Moreira, Paula I. | Aliev, Gjumrakch | Cash, Adam D. | Hirai, Keisuke | Smith, Mark A.

Article Type: Research Article

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. Show more

Keywords: Alzheimer disease, cell cycle re-entry, mitochondria, mitochondrial transport, mitochondrial turnover, oxidative stress

DOI: 10.3233/JAD-2006-9207

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 147-153, 2006

Authors: Ohta, Shigeo | Ohsawa, Ikuroh

Article Type: Research Article

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 β 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. Show more

Keywords: Aldehyde, ALDH2, case-control study, cytochrome c oxidase, DLST

DOI: 10.3233/JAD-2006-9208

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 155-166, 2006

Authors: de la Monte, Suzanne M. | Wands, Jack R.

Article Type: Research Article

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) α and δ genes were significantly reduced, whereas PPAR-γ 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. Show more

Keywords: Oxidative stress, insulin resistance, mitochondria, central nervous system, Alzheimer's disease, NADPH oxidase, real time RT-PCR

DOI: 10.3233/JAD-2006-9209

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 167-181, 2006

Authors: Onyango, Isaac | Khan, Shaharyar | Miller, Bradley | Swerdlow, Russell | Trimmer, Patricia | Bennett Jr., James

Article Type: Research Article

Abstract: Although mitochondrial dysfunction and increased oxidative stress are found in Alzheimer's disease (AD), the origin(s) of the mitochondrial dysfunction, its causal relationship to oxidative stress and the mechanisms of their downstream effects to yield synaptic dysfunction and neuronal death are not known with certainty. The discovery of “classic” mitochondrial diseases where bioenergetic deficiencies were associated with causal mutations or deletions in mitochondrial DNA (mtDNA) generated a search for similar abnormalities in AD samples. At least three-dozen studies since 1992 have failed to find consistent mutational abnormalities in AD mtDNA beyond those associated with aging, with most studies carried out in …postmortem brain. Historically, the publication of a new mutation or deletion is followed by other studies that fail to confirm the initial finding. Promising recent findings include heteroplasmic mutations in the D-loop control region. AD brain mtDNA consistently has more oxidative damage beyond that due to aging, providing the potential for generation of mutations/deletions and postgenomic problems with transcriptional regulation. To date no AD brain studies have examined individual neurons to search for clonal expansions of deleted mtDNA's like two recent reports in Parkinson's disease substantia nigra. Cybrid (cytoplasmic hybrid) models, in which mitochondrial DNA (mtDNA) from accessible tissue (platelets) of living AD patients is expressed in replicating human neural cells initially devoid of their own endogenous mtDNA (ρ° cells) revealed that decreased cytochrome oxidase (CO) activity, increased oxidative stress, increased beta amyloid production, activation of detrimental intracellular signaling and caspases, accelerated mtDNA proliferation, and abnormal mitochondrial morphology and transport can be transmitted through expression of mtDNA from living AD patients. Carrying these cybrid observations into AD brain is necessary to demonstrate any causality of brain mtDNA to contribute to pathogenesis. A novel protein transfection technology that allows transfer of mtDNA into mitochondria of cells (“protofection”) will allow this question to be examined. The contribution of altered mtDNA to pathogenesis and progression of AD is suggestive, not proven, and likely very heterogenous. Show more

DOI: 10.3233/JAD-2006-9210

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 183-193, 2006

Authors: DeWitt, David A. | Hurd, Jennifer A. | Fox, Nena | Townsend, Brigitte E. | Griffioen, Kathleen J.S. | Ghribi, Othman | Savory, John

Article Type: Research Article

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. Show more

Keywords: Apoptosis, axonal transport, Alzheimer's disease, aluminum, staurosporine

DOI: 10.3233/JAD-2006-9211

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 195-205, 2006

Authors: Blass, John P. | Gibson, Gary E.

Article Type: Research Article

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. Show more

DOI: 10.3233/JAD-2006-9212

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 207-218, 2006

Article Type: Discussion

DOI: 10.3233/JAD-2006-9213

Citation: Journal of Alzheimer's Disease, vol. 9, no. 2, pp. 219-224, 2006