Journal of Alzheimer's Disease - Volume 43, issue 4

Authors: Vicario-Orri, Elena | Opazo, Carlos M. | Muñoz, Francisco J.

Article Type: Review Article

Abstract: Neurons communicate in the nervous system by carrying out information along the length of their axons to finally transmit it at the synapse. Proper function of axons and axon terminals relies on the transport of proteins, organelles, vesicles, and other elements from the site of synthesis in the cell body. Conversely, neurotrophins secreted from axonal targets and other components at nerve terminals need to travel toward the cell body for clearance. Molecular motors, namely kinesins and dyneins, are responsible for the movement of these elements along cytoskeletal tracks. Given the challenging structure of neurons, axonal transport machinery plays a crucial …role in maintaining neuronal viability and function, allowing the proper neurotransmitter release at the presynaptic ending. On this basis, failure of axonal transport has been proposed as a key player in the development and/or progression of neurodegenerative disorders such as Alzheimer's disease (AD). Increasing evidence suggests that amyloid-β peptide, a hallmark of AD, may disrupt axonal transport and in so doing, contribute to AD pathophysiology. Here we discuss the molecular mechanisms of axonal transport with specific emphasis on the possible relationship between defective axonal transport and AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, axon, fast axonal transport, molecular motors

DOI: 10.3233/JAD-141080

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1097-1113, 2015

Authors: Bedse, Gaurav | Romano, Adele | Lavecchia, Angelo M. | Cassano, Tommaso | Gaetani, Silvana

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disease characterized by cognitive impairment and mental disorders. The actual cause and cascade of events in the progression of this pathology is not fully determined. AD is multifaceted in nature and is linked to different multiple mechanisms in the brain. This aspect is related to the lack of efficacious therapies that could slow down or hinder the disease onset/progression. The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway. Recently, the endocannabinoid system emerged as a novel …potential therapeutic target to treat AD. In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD, although the mechanisms that are involved are not fully elucidated. This review provides an update of this area. In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets. Show more

Keywords: 2-AG, Alzheimer's disease, amyloid-β, anandamide, cannabinoids, CB1, CB2, FAAH, MAGL, tau

DOI: 10.3233/JAD-141635

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1115-1136, 2015

Authors: Lan, Yu-Long | Zhao, Jie | Li, Shao

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and disordered cognition. Women have a higher AD incidence than men, indicating that the declining estrogen levels during menopause may influence AD pathogenesis. However, the mechanism underlying estrogen's neuroprotective effect is not fully clarified and is complicated by the presence of several distinct estrogen receptor (ER) types and the identification of a growing number of ER splice variants. Thus, a deeper analysis of ERs could elucidate the role of estrogen in age-related cognitive changes. Intracellular calcium signaling cascades play a pivotal role in ERα neuroprotection against AD. The …ERα-mediated inhibition of Death domain-associated protein (Daxx) translocation and the combination of membrane ERα and caveolin in caveolae may protect against AD. Moreover, the voltage-dependent anion channel (VDAC)/ERα association may be important for maintaining channel inactivation and may be relevant in neuronal preservation against Aβ injury. Additionally, ERα may prevent glutamate excitotoxic injury by Aβ through estrogen signaling mechanisms. ERα and IGF-IR co-activation may mediate neuroprotection, and many other growth factors and intracellular signaling responses triggered by ERα may also play important roles in this process. Furthermore, details regarding the genes and mRNA variants of ERα that are expressed in different parts of the human organs have been clarified recently. Therefore, here we review the literature to clarify the neuroprotective role of ERα. This review focuses on the potential mechanisms mediated by ERα in the intracellular signaling events in nervous system cells, thereby clarifying ERα-mediated protection against AD. Show more

Keywords: Alzheimer's disease, estrogen receptor alpha, neuroprotection, therapy

DOI: 10.3233/JAD-141875

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1137-1148, 2015

Authors: Deloncle, Roger | Guillard, Olivier

Article Type: Research Article

Abstract: In Alzheimer's (AD), Lewy body (LBD), and Creutzfeldt Jakob (CJD) diseases, similar pathological hallmarks have been described, one of which is brain deposition of abnormal protease-resistant proteins. For these pathologies, copper bound to proteins is able to protect against free radicals by reduction from cupric Cu++ to cupreous Cu+ . We have previously demonstrated in bovine brain homogenate that free radicals produce proteinase K-resistant prion after manganese is substituted for copper. Since low brain copper levels have been described in transmissible spongiform encephalopathies, in substantia nigra in Parkinson's disease, and in various brain regions in AD, LBD, and CJD, …a mechanism has been proposed that may underlie the neurodegenerative processes that occur when copper protection against free radicals is impaired. In peptide sequences, the alpha acid proton near the peptide bond is highly mobile and can be pulled out by free radicals. It will produce a trivalent α-carbon radical and induce a free radical chain process that will generate a D-amino acid configuration in the peptide sequence. Since only L-amino acids are physiologically present in mammalian (human) proteins, it may be supposed that only physiological L-peptides can be recycled by physiological enzymes such as proteases. If a D-amino acid is found in the peptide sequence subsequent to deficient copper protection against free radicals, it will not be recognized and might alter the proteasome L-amino acid recycling from brain peptides. In the brain, there will result an accumulation of abnormal protease-resistant proteins such as those observed in AD, LBD, and CJD. Show more

Keywords: Alzheimer's disease, copper deficiency, Creutzfeldt Jakob disease, D-amino acids, free radicals, Lewy body disease

DOI: 10.3233/JAD-140765

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1149-1156, 2015

Authors: Lejavova, Katarina | Ondicova, Katarina | Horvathova, Lubica | Hegedusova, Noemi | Cubinkova, Veronika | Vargovic, Peter | Manz, Georg | Filipcik, Peter | Mravec, Boris | Novak, Michal | Kvetnansky, Richard

Article Type: Short Communication

Abstract: Stress may accelerate onset of neurodegenerative diseases in vulnerable subjects and, vice versa, neurodegeneration affects the responsiveness to stressors. We investigated the neuroendocrine response to immobilization stress in normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and transgenic rats of respective WKY and SHR strains overexpressing human truncated tau protein. Plasma levels of epinephrine, norepinephrine, and corticosterone were determined. An immobilization-induced elevation of epinephrine and norepinephrine was significantly reduced in WKY transgenic rats compared to WKY wild-type rats, while no differences were seen between SHR transgenic and SHR wild-type animals. Our data have shown that sympathoadrenal system response to stress …strongly depends on both tau protein-induced neurodegeneration and genetic background of experimental animals. Show more

Keywords: Alzheimer's disease, corticosterone, epinephrine, hypothalamic-pituitary adrenocortical axis, norepinephrine, stress, sympathoadrenal system, tauopathy

DOI: 10.3233/JAD-141329

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1157-1161, 2015

Authors: Gough, Mallory | Blanthorn-Hazell, Sophee | Parkin, Edward T.

Article Type: Short Communication

Abstract: Amyloid-β protein precursor (AβPP) proteolysis by β- and γ-secretases generates neurotoxic amyloid-β (Aβ)-peptides in Alzheimer's disease (AD). We have investigated the role of histidine residues within the extracellular E1 copper binding and Aβ domains of AβPP in its proteolysis. By stably expressing histidine to alanine AβPP mutant constructs in SH-SY5Y cells, we show that mutations in the E1 copper binding domain had no impact on α- or β-secretase processing. Mutation of histidine 14 within the Aβ-domain specifically down-regulated β-secretase processing without impacting on non-amyloidogenic proteolysis. Understanding how histidine 14 participates in AβPP proteolysis may reveal new intervention points for AD …treatments. Show more

Keywords: Amyloid-β protein precursor, amyloidogenic processing, β-secretase, histidine 14

DOI: 10.3233/JAD-141650

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1163-1168, 2015

Authors: Piaceri, Irene | Raspanti, Beatrice | Tedde, Andrea | Bagnoli, Silvia | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) is a multifactorial disorder induced by a combination of genetic and environmental factors, and epigenetic modifications could be the key to understand the pathogenesis of AD. We performed a methylation study of the promoter regions of the three AD principal causative genes in 60 late-onset AD patients and 60 controls. The studied regions in the three causative genes were strongly unmethylated in both groups, but in AD patients the methylation resulted significantly increased. Our study adds new insights to previous ones by showing the involvement of epigenetic changes in AD, which influence the pathogenesis of the disease.

Keywords: Alzheimer's disease, AβPP, DNA methylation, epigenetics, PSEN1, PSEN2

DOI: 10.3233/JAD-141452

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1169-1173, 2015

Authors: Gallego-Jutglà, Esteve | Solé-Casals, Jordi | Vialatte, François-Benoît | Dauwels, Justin | Cichocki, Andrzej

Article Type: Research Article

Abstract: Despite recent advances, early diagnosis of Alzheimer's disease (AD) from electroencephalography (EEG) remains a difficult task. In this paper, we offer an added measure through which such early diagnoses can potentially be improved. One feature that has been used for discriminative classification is changes in EEG synchrony. So far, only the decrease of synchrony in the higher frequencies has been deeply analyzed. In this paper, we investigate the increase of synchrony found in narrow frequency ranges within the θ band. This particular increase of synchrony is used with the well-known decrease of synchrony in the α band to enhance detectable …differences between AD patients and healthy subjects. We propose a new synchrony ratio that maximizes the differences between two populations. The ratio is tested using two different data sets, one of them containing mild cognitive impairment patients and healthy subjects, and another one, containing mild AD patients and healthy subjects. The results presented in this paper show that classification rate is improved, and the statistical difference between AD patients and healthy subjects is increased using the proposed ratio. Show more

Keywords: Alzheimer's disease, data interpretation, electroencephalography, mild cognitive impairment, phase synchronization

DOI: 10.3233/JAD-140468

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1175-1184, 2015

Authors: Díaz, Mario | Fabelo, Noemí | Martín, Virginia | Ferrer, Isidre | Gómez, Tomás | Marín, Raquel

Article Type: Research Article

Abstract: In the present study, we have assessed the biophysical properties of lipid rafts from different brain areas in subjects exhibiting early neuropathological stages of Alzheimer's disease (AD). By means of steady-state fluorescence polarization analyses using two environment-sensitive fluorescent probes, we demonstrate that lipid rafts from cerebellum, and frontal and entorhinal cortices, exhibit different biophysical behaviors depending on the stage of the disease. Thus, while membrane anisotropies were similar in the cerebellum along stages, lipid rafts from frontal and entorhinal cortices at AD stages I/II and AD III were significantly more liquid-ordered than in control subjects, both at the aqueous interface …and hydrophobic core of the raft membrane. Thermotropic analyses demonstrated the presence of Arrhenius breakpoints between 28.3–32.0°C, which were not influenced by the disease stage. However, analyses of membrane microviscosity (ηapp ) demonstrate that frontal and entorhinal lipid rafts are notably more viscous and liquid-ordered all across the membrane from early stages of the disease. These physicochemical alterations in lipid rafts do not correlate with changes in cholesterol or sphingomyelin levels, but to reduced unsaturation index and increased saturate/polyunsaturated ratios in phospholipid acyl chains. Moreover, we demonstrate that β-secretase/AβPP (amyloid-β protein precursor) interaction and lipid raft microviscosity are strongly, and positively, correlated in AD frontal and entorhinal cortices. These observations strengthens the hypothesis that physical properties of these microdomains modulate the convergence of amyloidogenic machinery toward lipid rafts, and also points to a critical role of polyunsaturated fatty acids in amyloidogenic processing of AβPP. Show more

Keywords: BACE1, β-secretase, cerebellum, docosahexaenoic acid, entorhinal cortex, fluorescence anisotropy, frontal cortex, lipid rafts, membrane viscosity, polyunsaturated fatty acids

DOI: 10.3233/JAD-141146

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1185-1198, 2015

Authors: Gironi, Maira | Borgiani, Bruno | Farina, Elisabetta | Mariani, Enrica | Cursano, Cristina | Alberoni, Margherita | Nemni, Raffaello | Comi, Giancarlo | Buscema, Massimo | Furlan, Roberto | Grossi, Enzo

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia, while mild cognitive impairment (MCI) causes a slight but measurable decline in cognitive abilities. A person with MCI has an increased risk of developing AD or another dementia. Thus, it is of medical interest to develop predictive tools to assess this risk. A growing awareness exists that pro-oxidative state and neuro-inflammation are both involved in AD. However, the extent of this relationship is still a matter of debate. Due to the expected non-linear correlations between oxidative and inflammatory markers, traditional statistics is unsuitable to dissect their relationship with the disease. …Artificial neural networks (ANNs) are computational models inspired by central nervous system networks, capable of machine learning and pattern recognition. The aim of this work was to disclose the relationship between immunological and oxidative stress markers in AD and MCI by the application of ANNs. Through a machine learning approach, we were able to construct an algorithm to classify MCI and AD with high accuracy. Such an instrument, requiring a small amount of immunological and oxidative-stress parameters, would be useful in the clinical practice. Moreover, applying an innovative non-linear mathematical technique, a global immune deficit was shown to be associated with cognitive impairment. Surprisingly, both adaptive and innate immunity were peripherally defective in AD and MCI patients. From this study, new pathogenetic aspects of these diseases could emerge. Show more

Keywords: Artificial neural network, machine learning, oxidative-stress, neurodegeneration, pattern recognition, relationships

DOI: 10.3233/JAD-141116

Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1199-1213, 2015