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

Authors: Viña, Jose | Lloret, Ana

Article Type: Review Article

Abstract: The main risk factors for developing Alzheimer's disease (AD) are age and gender. The incidence of the disease is higher in women than in men, and this cannot simply be attributed to the higher longevity of women versus men. Thus, there must be a specific pathogenic mechanism to explain the higher incidence of AD cases in women. In this regard, it is notable that mitochondria from young females are protected against amyloid-β toxicity, generate less reactive oxygen species, and release less apoptogenic signals than those from males. However, all this advantage is lost in mitochondria from old females. Since estrogenic …compounds protect against mitochondrial toxicity of amyloid-β, estrogenic action may be important in protecting cells from amyloid-β toxicity and suggests a possible treatment or prevention strategy for AD. Unfortunately, to date, clinical trials with Ginkgo biloba and other estrogenic therapies have not proved successful in treating AD. As such, more experiments and clinical trials are indeed warranted to find conditions in which estrogenic compounds may be useful to prevent or treat AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, gender, mitochondria

DOI: 10.3233/JAD-2010-100501

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S527-S533, 2010

Authors: Dragicevic, Natasa | Mamcarz, Malgorzata | Zhu, Yuyan | Buzzeo, Robert | Tan, Jun | Arendash, Gary W. | Bradshaw, Patrick C.

Article Type: Research Article

Abstract: Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain, and the amyloid-β (Aβ) peptide is known to induce mitochondrial dysfunction. The relative degree of mitochondrial dysfunction in different regions of the brain in AD is not completely understood. Moreover, the relationship between levels of synaptic mitochondrial Aβ and mitochondrial dysfunction has not been clearly established. Therefore synaptic and nonsynaptic mitochondria were isolated from the hippocampus, cortex, striatum, and amygdala of 12 month AβPPsw and AβPP+PS1 mouse models of AD as well as nontransgenic mice. Mitochondrial respiratory rates, reactive oxygen species production, membrane potential, and cytochrome c oxidase activity were measured. …Hippocampal and cortical mitochondria showed the highest levels of mitochondrial dysfunction, while striatal mitochondria were moderately affected, and amygdalar mitochondria were minimally affected. Mitochondria from AβPP/PS1 brain regions were more impaired than those from AβPP mice. Mitochondrial Aβ levels nearly mirrored the extent of mitochondrial dysfunction. Synaptic mitochondria were more impaired than nonsynaptic mitochondria in the AD mouse models. The AβPP/PS1 mice showed more impairment in the cognitive interference task of working memory than the AβPP mice. The association between mitochondrial Aβ levels and mitochondrial dysfunction in mouse models of AD supports a primary role for mitochondrial Aβ in AD pathology. Moreover, the degree of cognitive impairment in AD transgenic mice can be linked to the extent of synaptic mitochondrial dysfunction and mitochondrial Aβ levels, suggesting that a mitochondrial Aβ-induced signaling cascade may contribute to cognitive impairment. Therapeutics that target this cascade could be beneficial in the treatment of AD. Show more

Keywords: Alzheimer's disease, amygdala, cognitive function, cytochrome oxidase, membrane potential, mitochondrial, reactive oxygen species, respiration, striatum, synapse

DOI: 10.3233/JAD-2010-100342

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S535-S550, 2010

Authors: Horowitz, Maxx P. | Greenamyre, J. Timothy

Article Type: Review Article

Abstract: In addition to their well-established role in providing the cell with ATP, mitochondria are the source of iron-sulfur clusters (ISCs) and heme – prosthetic groups that are utilized by proteins throughout the cell in various critical processes. The post-transcriptional system that mammalian cells use to regulate intracellular iron homeostasis depends, in part, upon the synthesis of ISCs in mitochondria. Thus, proper mitochondrial function is crucial to cellular iron homeostasis. Many neurodegenerative diseases are marked by mitochondrial impairment, brain iron accumulation, and oxidative stress – pathologies that are inter-related. This review discusses the physiological role that mitochondria play in cellular iron …homeostasis and, in so doing, attempts to clarify how mitochondrial dysfunction may initiate and/or contribute to iron dysregulation in the context of neurodegenerative disease. We review what is currently known about the entry of iron into mitochondria, the ways in which iron is utilized therein, and how mitochondria are integrated into the system of iron homeostasis in mammalian cells. Lastly, we turn to recent advances in our understanding of iron dysregulation in two neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), and discuss the use of iron chelation as a potential therapeutic approach to neurodegenerative disease. Show more

Keywords: Alzheimer's disease, FBXL5, iron, iron regulatory protein, iron-sulfur cluster, mitochondria, neurodegeneration, Parkinson's disease

DOI: 10.3233/JAD-2010-100354

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S551-S568, 2010

Authors: Chen, John Xi | Yan, Shirley Shidu

Article Type: Review Article

Abstract: Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Abnormalities in mitochondrial properties include impaired energy metabolism, defects in key respiratory enzyme activity/function, accumulation/generation of mitochondrial reactive oxygen species, and formation of membrane permeability transition pore. While the mechanisms underlying mitochondrial dysfunction remain incompletely understood, recent studies provide substantial evidence for the progressive accumulation of mitochondrial Aβ, which directly links to mitochondria-mediated toxicity. In this review, we describe recent studies addressing the following key questions: 1) Does Aβ accumulate in mitochondria of AD brain and AD mouse models?; 2) How does Aβ gain access to the mitochondria?; 3) If …mitochondria are loaded with Aβ, do they develop similar evidence of dysfunction?; 4) What are the mechanisms underlying mitochondrial Aβ-induced neuronal toxicity?; and 5) What is the impact of interaction of mitochondrial Aβ with its binding partners (cyclophilin D and ABAD) on mitochondrial and neuronal properties/function in an Aβ milieu? The answers to these questions provide new insights into mechanisms of mitochondrial stress related to the pathogenesis of AD and information necessary for developing therapeutic strategy for AD. Show more

Keywords: Alzheimer's disease, amyloid, cyclophilin, mitochondria, toxicity

DOI: 10.3233/JAD-2010-100357

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S569-S578, 2010

Authors: Ankarcrona, Maria | Mangialasche, Francesca | Winblad, Bengt

Article Type: Review Article

Abstract: The number of people suffering from Alzheimer's disease (AD) is constantly increasing worldwide since humans live longer and age is the strongest risk factor for AD. Currently available medications for AD do not interfere with the progressive loss of synapses and neurons in the AD brain. Therefore, the development of disease modifying therapies is a major future goal. Mitochondria provide cellular energy and are crucial for proper neuronal activity and survival. Mitochondrial dysfunction is evident in early stages of AD and is involved in AD pathogenesis. The development of drugs that protect mitochondria from damage is therefore a promising strategy …for AD therapy. In this review, we will discuss current available medications for AD, drugs under clinical testing, and mitochondria as a novel drug target. Show more

Keywords: Alzheimer's disease, drug target, mitochondria, therapy

DOI: 10.3233/JAD-2010-100327

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S579-S590, 2010

Authors: Gibson, Gary E. | Shi, Qingli

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is defined by senile plaques made of amyloid-β peptide (Aβ), neurofibrillary tangles made of hyperphosphorylated tau proteins, and memory deficits. Thus, the events initiating the cascade leading to these end points may be more effective therapeutic targets than treating each facet individually. In the small percentage of cases of AD that are genetic (or animal models that reflect this form of AD), the factor initiating AD is clear (e.g., genetic mutations lead to high Aβ1-42 or hyperphosphorylated tau proteins). In the vast majority of AD cases, the cause is unknown. Substantial evidence now suggests that abnormalities …in glucose metabolism/mitochondrial function/oxidative stress (GMO) are an invariant feature of AD and occur at an early stage of the disease process in both genetic and non-genetic forms of AD. Indeed, decreases in brain glucose utilization are diagnostic for AD. Changes in calcium homeostasis also precede clinical manifestations of AD. Abnormal GMO can lead to plaques, tangles, and the calcium abnormalities that accompany AD. Abnormalities in GMO diminish the ability of the brain to adapt. Therapies targeting mitochondria may ameliorate abnormalities in plaques, tangles, calcium homeostasis, and cognition that comprise AD. Show more

Keywords: Alzheimer's disease, amyloid, calcium, mitochondria, oxidative stress, neurofibrillary tangles, senile plaques

DOI: 10.3233/JAD-2010-100336

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S591-S607, 2010

Authors: Manczak, Maria | Mao, Peizhong | Calkins, Markus J. | Cornea, Anda | Reddy, Arubala P. | Murphy, Michael P. | Szeto, Hazel H. | Park, Byung | Reddy, P. Hemachandra

Article Type: Research Article

Abstract: The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants, MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model (Tg2576 line) of Alzheimer's disease (AD) and on mouse neuroblastoma (N2a) cells incubated with the amyloid-β (Aβ) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ. In N2a cells only incubated with the Aβ, we found increased expressions of mitochondrial fission genes and decreased expression of …fusion genes and also decreased expression of peroxiredoxins. Electron microscopy of the N2a cells incubated with Aβ revealed a significantly increased number of mitochondria, indicating that Aβ fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Aβ-incubated N2a cells, indicating that Aβ affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid-β precursor protein transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that MitoQ and SS31 prevent Aβ toxicity, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, cyclophilin D, mitochondria-targeted antioxidants, peroxiredoxins

DOI: 10.3233/JAD-2010-100564

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S609-S631, 2010

Authors: Dumont, Magali | Lin, Michael T. | Beal, M. Flint

Article Type: Review Article

Abstract: Oxidative stress and mitochondrial dysfunction are important features present in Alzheimer's disease (AD). They appear early and contribute to disease progression, both in human postmortem AD brains as well as in transgenic AD mouse brains. For this reason, targeting oxidative stress and mitochondria in AD may lead to the development of promising therapeutic strategies. Several exogenous antioxidant compounds have been tested and found beneficial in transgenic AD mice, such as vitamins and spices. However, their efficacy was much more modest in human trials. More recently, new strategies have been elaborated to promote endogenous antioxidant systems. Different pathways involved in oxidative …stress response have been identified. Compounds able to upregulate these pathways are being generated and tested in animal models of AD and in human patients. Upregulation of antioxidant gene expression was beneficial in mice, giving hope for future avenues in the treatment of AD and other neurodegenerative disorders. Show more

Keywords: Alzheimer's disease, antioxidants, mitochondria, oxidative stress, therapeutic strategies, transgenic mice

DOI: 10.3233/JAD-2010-100507

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S633-S643, 2010