Journal of Alzheimer's Disease - Volume 20, issue s2

Authors: Young, Kisha J. | Bennett, James P.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is …supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction. Show more

Keywords: Alzheimer's disease, amyloid-β, γ-secretase, mitochondria, mitochondria-respiration

DOI: 10.3233/JAD-2010-100360

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S381-S400, 2010

Authors: Santos, Renato X. | Correia, Sónia C. | Wang, Xinglong | Perry, George | Smith, Mark A. | Moreira, Paula I. | Zhu, Xiongwei

Article Type: Review Article

Abstract: Alzheimer's disease (AD), the most common form of dementia in the elderly, can have a late-onset sporadic or an early-onset familial origin. In both cases, the neuropathological hallmarks are the same: senile plaques and neurofibrillary tangles. Despite AD having a proteinopathic nature, there is strong evidence for an organelle dysfunction-related neuropathology, namely dysfunctional mitochondria. In this regard, dysfunctional mitochondria and associated exacerbated generation of reactive oxygen species are among the earliest events in the progression of the disease. Since the maintenance of a healthy mitochondrial pool is essential given the central role of this organelle in several determinant cellular processes, …mitochondrial dysfunction in AD would be predicted to have profound pluripotent deleterious consequences. Mechanistically, recent reports suggest that mitochondrial fission/fusion and mitophagy are altered in AD and in in vitro models of disease, and since both processes are reported to be protective, this review will discuss the role of mitochondrial fission/fusion and mitophagy in the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, fission, fusion, mitochondrial dysfunction, mitophagy

DOI: 10.3233/JAD-2010-100666

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S401-S412, 2010

Authors: Adam-Vizi, Vera | Starkov, Anatoly A.

Article Type: Review Article

Abstract: A number of recent discoveries indicate that abnormal Ca2+ signaling, oxidative stress, and mitochondrial dysfunction are involved in the neuronal damage in Alzheimer's disease. However, the literature on the interactions between these factors is controversial especially in the interpretation of the cause-effect relationship between mitochondrial damage induced by Ca2+ overload and the production of reactive oxygen species (ROS). In this review, we survey the experimental observations on the Ca2+ -induced mitochondrial ROS production, explain the sources of controversy in interpreting these results, and discuss the different molecular mechanisms underlying the effect of Ca2+ on the ROS emission …by brain mitochondria. Show more

Keywords: Calcium, mitochondria, permeability transition, reactive oxygen species

DOI: 10.3233/JAD-2010-100465

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S413-S426, 2010

Authors: Greco, Tiffany | Fiskum, Gary

Article Type: Review Article

Abstract: Oxidative stress and loss of cellular Ca2+ homeostasis are closely linked and are common denominators in the pathophysiology of many neurodegenerative diseases and acute disorders of the nervous system. Mitochondria are major targets of oxidative stress and abnormal intracellular Ca2+ , as both can cause bioenergetic failure through synergistic activation of the mitochondrial inner membrane permeability transition pore. Opening of this molecularly ill-defined pore causes both collapse of the membrane potential, which drives oxidative phosphorylation, and release of small metabolites, including pyridine nucleotides and glutathione, which are necessary for energy metabolism and defense against oxidative stress. Expression of genes …coding for many antioxidant defense proteins is regulated by the Nrf2 transcriptional activating factor. Translocation of this protein from the cytosol to the nucleus is stimulated by oxidative stress and by specific agents that either react with cysteine sulfhydryl groups present on the protein KEAP1, that normally binds and restricts Nrf2 translocation, or that stimulate serine phosphorylation of Nrf2. Recent evidence indicates that mitochondria are a target of the cytoprotective gene expression induced by Nrf2 and that this pathway can increase resistance to redox-regulated opening of the permeability transition pore. Pharmacologic stimulation of the Nrf2 system and its protection against mitochondrial bioenergetic dysfunction may therefore constitute a powerful mechanism for both pre-conditioning against neurodegeneration and for post-conditioning against neural cell death associated with acute neurologic injury. Show more

Keywords: Antioxidant, bioenergetics, calcium, cerebral ischemia, neurodegeneration, Nrf2, oxidative stress, permeability transition pore

DOI: 10.3233/JAD-2010-100519

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S427-S437, 2010

Authors: Atamna, Hani | Kumar, Raj

Article Type: Review Article

Abstract: The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-β (Aβ) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. We have shown that MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration, which are impaired in AD brains. Consistently, MB is one of the most effective agents to delay senescence in normal human …cells. A key action of MB appears to be enhancing mitochondrial function, which is achieved at nM concentrations. We propose that the cycling of MB between the reduced leucomethylene blue (MBH2 ) and the oxidized (MB) forms may explain, in part, the mitochondria-protecting activities of MB. The second approach is use of naturally occurring osmolytes to prevent the formation of toxic forms of Aβ. Osmolytes (e.g., taurine, carnosine) are brain metabolites typically accumulated in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation, without perturbing other cellular processes. Experimental evidence suggests that the level of carnosine is significantly lower in AD patients. Osmolytes may inhibit the formation of Aβ species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Aβ. The potential significance of combining MB and osmolytes to treat AD are discussed. Show more

Keywords: Alzheimer's disease, amyloid-β, heme, methylene blue, mitochondria, osmolytes, oxidase, peroxidase

DOI: 10.3233/JAD-2010-100414

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S439-S452, 2010

Authors: Higgins, Gavin C. | Beart, Philip M. | Shin, Yea Seul | Chen, Minghui Jessica | Cheung, Nam Sang | Nagley, Phillip

Article Type: Review Article

Abstract: Oxidative stress plays a central role in neuronal injury and cell death in acute and chronic pathological conditions. The cellular responses to oxidative stress embrace changes in mitochondria and other organelles, notably endoplasmic reticulum, and can lead to a number of cell death paradigms, which cover a spectrum from apoptosis to necrosis and include autophagy. In Alzheimer's disease, and other pathologies including Parkinson's disease, protein aggregation provides further cellular stresses that can initiate or feed into the pathways to cell death engendered by oxidative stress. Specific attention is paid here to mitochondrial dysfunction and programmed cell death, and the diverse …modes of cell death mediated by mitochondria under oxidative stress. Novel insights into cellular responses to neuronal oxidative stress from a range of different stressors can be gained by detailed transcriptomics analyses. Such studies at the cellular level provide the key for understanding the molecular and cellular pathways whereby neurons respond to oxidative stress and undergo injury and death. These considerations underpin the development of detailed knowledge in more complex integrated systems, up to the intact human bearing the neuropathology, facilitating therapeutic advances. Show more

Keywords: Apoptosis, autophagy, mitochondria, necrosis, neurodegeneration, neurons, oxidative stress, programmed cell death

DOI: 10.3233/JAD-2010-100321

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S453-S473, 2010

Authors: Correia, Sónia C. | Santos, Renato X. | Perry, George | Zhu, Xiongwei | Moreira, Paula I. | Smith, Mark A.

Article Type: Review Article

Abstract: The quote “what does not kill you makes you stronger” perfectly describes the preconditioning phenomenon – a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Over the last few decades, many attempts have been made to identify the molecular mechanisms involved in preconditioning-induced protective responses, and recent data suggests that many of these mechanisms converge on the mitochondria, positing mitochondria as master regulators of preconditioning-triggered endogenous neuroprotection. In this review, we critically discuss evidence for the involvement of mitochondria within the preconditioning paradigm. We will highlight the crucial targets and mediators by which mitochondria are integrated …into neuroprotective signaling pathways that underlie preconditioning, putting focus on mitochondrial respiratory chain and mitochondrial reactive oxygen species, mitochondrial ATP-sensitive potassium channels, mitochondrial permeability transition pore, uncoupling proteins, and mitochondrial antioxidant enzyme manganese superoxide dismutase. We also discuss the role of mitochondria in the induction of hypoxia-inducible factor-1, a transcription factor engaged in preconditioning-mediated neuroprotective effects. The identification of intrinsic mitochondrial mechanisms involved in preconditioning will provide new insights which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration. Show more

Keywords: Hypoxia inducible factor-1, mitochondria, neuroprotection, preconditioning, reactive oxygen species

DOI: 10.3233/JAD-2010-100669

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S475-S485, 2010

Authors: Supnet, Charlene | Bezprozvanny, Ilya

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder among the aged worldwide. AD is characterized by extensive synaptic and neuronal loss that leads to impaired memory and cognitive decline. The cause of AD is not completely understood and no effective therapy has been developed. The accumulation of toxic amyloid-β42 (Aβ42 ) peptide oligomers and aggregates in AD brain has been proposed to be primarily responsible for the pathology of the disease, an idea dubbed the 'amyloid hypothesis' of AD etiology. In addition to the increase in Aβ42 levels, disturbances in neuronal calcium (Ca2+ ) signaling and alterations …in expression levels of Ca2+ signaling proteins have been observed in animal models of familial AD and in studies of postmortem brain samples from sporadic AD patients. Based on these data, the 'Ca2+ hypothesis of AD' has been proposed. In particular, familial AD has been linked with enhanced Ca2+ release from the endoplasmic reticulum and elevated cytosolic Ca2+ levels. The augmented cytosolic Ca2+ levels can trigger signaling cascades that affect synaptic stability and function and can be detrimental to neuronal health, such as activation of calcineurin and calpains. Here we review the latest results supporting the 'Ca2+ hypothesis' of AD pathogenesis. We further argue that over time, supranormal cytosolic Ca2+ signaling can impair mitochondrial function in AD neurons. We conclude that inhibitors and stablizers of neuronal Ca2+ signaling and mitochondrial function may have therapeutic potential for AD treatment. We also discuss latest and planned AD therapeutic trials of agents targeting Ca2+ channels and mitochondria. Show more

Keywords: Alzheimer's disease, calcium, Dimebon, endoplasmic reticulum, excitotoxicity, mitochondria

DOI: 10.3233/JAD-2010-100306

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S487-S498, 2010

Authors: Reddy, P. Hemachandra | Manczak , Maria | Mao, Peizhong | Calkins, Marcus J. | Reddy, Arubala P. | Shirendeb, Ulziibat

Article Type: Review Article

Abstract: This article reviews the role of amyloid-β (Aβ) and mitochondria in synaptic damage and cognitive decline found in patients with Alzheimer's disease (AD). Recent molecular, cellular, animal model, and postmortem brain studies have revealed that Aβ and mitochondrial abnormalities are key factors that cause synaptic damage and cognitive decline in AD. Aβ is reported to accumulate in subcellular compartments and to impair the normal function of neurons in AD patients. Further, recent studies using biochemical methods and electron microscopy have revealed that the accumulation of Aβ at nerve terminals affect synaptic activities, including the release of neurotransmitters and synaptic vesicles. …Recent studies of the relationship between mitochondria and Aβ in AD patients suggest that in mitochondria, structural changes caused by Aβ result in increased mitochondrial fragmentation, decreased mitochondrial fusion, mitochondrial dysfunction, and synaptic damage. This paper discusses the latest research on Aβ, mitochondria, age-dependent factors of AD in the brain, and synaptic damage in AD. This paper also briefly discusses potential mitochondrial therapeutics in the treatment of patients with AD. Show more

Keywords: Amyloid-β, amyloid-β precursor protein, mitochondrial therapeutics, synaptic pathology

DOI: 10.3233/JAD-2010-100504

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S499-S512, 2010

Authors: Bossy, Blaise | Petrilli, Alejandra | Klinglmayr, Eva | Chen, Jin | Lütz-Meindl, Ursula | Knott, Andrew B. | Masliah, Eliezer | Schwarzenbacher, Robert | Bossy-Wetzel, Ella

Article Type: Research Article

Abstract: Mitochondrial dysfunction and synaptic loss are among the earliest events linked to Alzheimer's disease (AD) and might play a causative role in disease onset and progression. The underlying mechanisms of mitochondrial and synaptic dysfunction in AD remain unclear. We previously reported that nitric oxide (NO) triggers persistent mitochondrial fission and causes neuronal cell death. A recent article claimed that S-nitrosylation of dynamin related protein 1 (DRP1) at cysteine 644 causes protein dimerization and increased GTPase activity and is the mechanism responsible for NO-induced mitochondrial fission and neuronal injury in AD, but not in Parkinson's disease (PD). However, this report remains …controversial. To resolve the controversy, we investigated the effects of S-nitrosylation on DRP1 structure and function. Contrary to the previous report, S-nitrosylation of DRP1 does not increase GTPase activity or cause dimerization. In fact, DRP1 does not exist as a dimer under native conditions, but rather as a tetramer capable of self-assembly into higher order spiral- and ring-like oligomeric structures after nucleotide binding. S-nitrosylation, as confirmed by the biotin-switch assay, has no impact on DRP1 oligomerization. Importantly, we found no significant difference in S-nitrosylated DRP1 (SNO-DRP1) levels in brains of age-matched normal, AD, or PD patients. We also found that S-nitrosylation is not specific to DRP1 because S-nitrosylated optic atrophy 1 (SNO-OPA1) is present at comparable levels in all human brain samples. Finally, we show that NO triggers DRP1 phosphorylation at serine 616, which results in its activation and recruitment to mitochondria. Our data indicate the mechanism underlying nitrosative stress-induced mitochondrial fragmentation in AD is not DRP1 S-nitrosylation. Show more

Keywords: Large GTPases, mitochondrial fission and fusion, nitrosative stress, OPA1, SNO-DRP1, synapses

DOI: 10.3233/JAD-2010-100552

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S513-S526, 2010