Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity

The endoplasmic reticulum (ER) is a well-orchestrated protein-folding machine composed of protein chaperones, proteins that catalyze protein folding, and sensors that detect the presence of misfolded or unfolded proteins. A sensitive surveillance mechanism exists to prevent misfolded proteins from transiting the secretory pathway and ensures that persistently misfolded proteins are directed toward a degradative pathway. The unfolded protein response (UPR) is an intracellular signaling pathway that coordinates ER protein-folding demand with protein-folding capacity and is essential to adapt to homeostatic alterations that cause protein misfolding. These include changes in intraluminal calcium, altered glycosylation, nutrient deprivation, pathogen infection, expression of folding-defective proteins, and changes in redox status. The ER provides a unique oxidizing folding-environment that favors the formation of the disulfide bonds. Accumulating evidence suggests that protein folding and generation of reactiv...

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Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?

Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.

Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease

Genetic and lifestyle-related risk factors for Alzheimer disease (AD) are associated with an increase in oxidative stress, suggesting that oxidative stress is involved at an early stage of the pathologic cascade. Moreover, oxidative stress is mechanistically and chronologically associated with other key features of AD, namely, metabolic, mitochondrial, metal, and cell-cycle abnormalities. Contrary to the commonly held notion that pathologic hallmarks of AD signify etiology, several lines of evidence now indicate that aggregation of amyloid-β and tau is a compensatory response to underlying oxidative stress. Therefore, removal of proteinaceous accumulations may treat the epiphenomenon rather than the disease and may actually enhance oxidative damage. Although some antioxidants have been shown to reduce the incidence of AD, the magnitude of the effect may be modified by individual factors such as genetic predisposition (e.g. apolipoprotein E genotype) and habitual behaviors. Because caloric restriction, exercise, and intellectual activity have been experimentally shown to promote neuronal survival through enhancement of endogenous antioxidant defenses, a combination of dietary regimen of low total calorie and rich antioxidant nutrients and maintaining physical and intellectual activities may ultimately prove to be one of the most efficacious strategies for AD prevention.

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Involvement of Oxidative Stress in Alzheimer Disease

Although the brain has been considered an insulin-insensitive organ, recent reports on the location of insulin and its receptors in the brain have introduced new ways of considering this hormone responsible for several functions The origin of insulin in the brain has been explained from peripheral or central sources, or both Regardless of whether insulin is of peripheral origin or produced in the brain, this hormone may act through its own receptors present in the brain The molecular events through which insulin functions in the brain are the same as those operating in the periphery However, certain insulin actions are different in the CNS, such as hormone-induced glucose uptake due to a low insulin-sensitive GLUT-4 activity, and because of the predominant presence of GLUT-1 and GLUT-3 In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes (T2DM) and Alzheimer’s disease (AD) A close association between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients, and some authors have proposed the name “type 3 diabetes” for this association There are links between AD and type 2 diabetes mellitus (T2DM) through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein OGlcNAcylation, formation of amyloid plaques, altered Aβ metabolism, and tau hyperphosphorylation Advances in the knowledge of preclinical AD and T2DM may be a major stimulus for the development of treatment for preventing the pathogenic events of

/pdf/insulin-in-the-brain-its-pathophysiological-implications-for-52adrugpil.pdf

Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease.

As major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and may therefore be particularly susceptible to oxidative damage. Mitochondrial damage could play a pivotal role in the cell death decision. A decrease in mitochondrial energy charge and redox state, loss of transmembrane potential (depolarization), mitochondrial respiratory chain impairment, and release of substances such as calcium and cytochrome c all contribute to apoptosis. These mitochondrial abnormalities may constitute a part of the spectrum of chronic oxidative stress in Alzheimer's disease. Accumulation of amyloid beta (Abeta) in form of senile plaques is also thought to play a central role in the pathogenesis of Alzheimer's disease mediated by oxidative stress. In addition, increasing evidence shows that Abeta generates free radicals in vitro, which mediate the toxicity of this peptide. In our study, PC12 cells were used to examine the protective features of EGb 761(definition see editorial) on mitochondria stressed with hydrogen peroxide and antimycin, an inhibitor of complex III. In addition, we investigated the efficacy of EGb 761 in Abeta-induced MTT reduction in PC12 cells. Moreover, we examined the effects of EGb 761 on ROS levels and ROS-induced apoptosis in lymphocytes from aged mice after in vivo administration. Here, we will report that EGb 761 was able to protect mitochondria from the attack of hydrogen peroxide, antimycin and Abeta. Furthermore, EGb 761 reduced ROS levels and ROS-induced apoptosis in lymphocytes from aged mice treated orally with EGb 761 for 2 weeks. Our data further emphasize neuroprotective properties of EGb 761, such as protection against Abeta-toxicity, and antiapoptotic properties, which are probably due to its preventive effects on mitochondria.

/pdf/effects-of-egb-761-ginkgo-biloba-extract-on-mitochondrial-1zy90dkxfu.pdf

Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress.

The causal relationship between amyloid beta-peptide (Aβ) deposition and Alzheimer's disease (AD)-specific neuropathological lesions such as neurodegeneration and cortical atrophy is still not known. Mounting evidence points to alterations in cholesterol homeostasis occurring in AD brain that are probably linked to cerebral Aβ pathology. Interestingly, cholesterol not only modulates Aβ synthesis, but also controls interactions between Aβ and neuronal membranes that are regarded as decisive in the initiation of a neurotoxic cascade. This review focuses on the impact of cholesterol on membrane disordering effects of Aβ. Cholesterol is known to be an essential modulator of physicochemical state and functional activity in physiological membranes, and thus plays an essential role in the regulation of synaptic function and cell plasticity. In vitro and in vivo modulation of membrane cholesterol levels affect different cholesterol pools within the plasma membrane bilayer that are differentially sensitive to Aβ's disrupting effects. Membrane acyl-chains in the hydrocarbon core are most susceptible to Aβ. In this membrane region, cholesterol attenuates the membrane disordering effects of Aβ. This cholesterol pool is modulated by methyl-beta-cyclodextrin (MβCD) treatment in vitro. On the other hand, statin treatment in vivo depletes a cholesterol pool in a membrane area, which is much less susceptible to Aβ's membrane-disrupting effects. Our findings clearly implicate an involvement of cholesterol in brain membrane alterations occurring during AD. Disease-related changes in membrane cholesterol metabolism may be subtle and restricted to defined membrane pools since total membrane cholesterol levels are mainly unchanged in AD brain. Thus, elucidation of the structure and function of different cholesterol pools is necessary in understanding the coherence between cholesterol and AD.

Cholesterol modulates amyloid beta-peptide's membrane interactions.

The Swedish double mutation (KM670/671NL) of amyloid precursor protein (APPsw) is associated with early-onset familial Alzheimer's disease (FAD) and results in from three- to sixfold increased beta-amyloid production. The goal of the present study was to elucidate the effects of APPsw on mechanisms of apoptotic cell death. Therefore, PC12 cells were stably transfected with human APPsw. Here we report that the vulnerability of APPsw-bearing PC12 cells to undergo apoptotic cell death was significantly enhanced after exposure to hydrogen peroxide compared to human wild-type APP-bearing cells, empty vector-transfected cells, and parent untransfected cells. In addition, we have analyzed the potential influence of several mechanisms that can interfere with the execution of the apoptotic cell death program: the inhibition of cell death by the use of caspase inhibitors and the reduction of oxidative stress by the use of (+/-)-alpha-tocopherol (vitamin E). Interestingly, oxidative stress-induced cell death was significantly attenuated in APPsw PC12 cells by pretreatment with caspase-3 inhibitors but not with caspase-1 inhibitors. In parallel, caspase-3 activity was markedly elevated in APPsw PC12 after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (+/-)-alpha-tocopherol. The protective potency of (+/-)-alpha-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.

Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation.

Mutations in the amyloid precursor protein (APP) gene are known as causative factors in the pathogenesis of early-onset familial Alzheimer’s disease (FAD). In this study, the influence of the Swedish double-mutation form of APP (APPsw; KM670/671NL) on apoptosis regulation in PC12 cells was investigated. APPsw-transfected PC12 cells were compared with wild-type APP (APPwt)-expressing and vector-transfected PC12 cells with regard to their susceptibility to cell death induced by the reduction of trophic support or by additional treatment with staurosporine. Expression of APPsw markedly enhanced the level of apoptotic PC12 cells induced by serum reduction. A similar hypersensitivity of APPsw-expressing PC12 cells could be detected after differentiation with nerve growth factor under serum-reduced conditions. Likewise, the expression of APPsw rendered PC12 cells more vulnerable to staurosporine but only under serum-reduced conditions. This APPsw-effect disappeared in high serum-containing medium. Thus, expression of APPsw seems to enhance cellular sensitivity not in general but after the reduction of trophic factors probably by causing oxidative stress. This, in turn, may sensitize cells to secondary apoptotic stimuli. Moreover, the mutation-specific increase in vulnerability to cell death was only seen at the stage of apoptotic nuclei, but not using methods measuring cell death by determining metabolic activity or membrane integrity. Therefore, the expression of APPsw seems to affect specifically apoptotic cell death rather than overall cell death in vitro. Our study further emphasizes the pathogenic role of mutant APP and may provide new insights in the mechanisms underlying the massive neurodegeneration in brain from patients bearing the APPsw mutation.

Reduction of trophic support enhances apoptosis in PC12 cells expressing Alzheimer’s APP mutation and sensitizes cells to staurosporine-induced cell death

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Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress.

Cholesterol modulates amyloid beta-peptide's membrane interactions.

Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation.

Reduction of trophic support enhances apoptosis in PC12 cells expressing Alzheimer’s APP mutation and sensitizes cells to staurosporine-induced cell death