Journal of Alzheimer's Disease - Volume 20, issue 4

Authors: Coppedè, Fabio | Migliore, Lucia

Article Type: Review Article

Abstract: Increasing evidence suggests that the repair of DNA lesions, particularly oxidative DNA lesions, might be compromised in Alzheimer's disease (AD). Studies performed in brains and peripheral tissues of both AD patients and individuals affected by mild cognitive impairment (MCI) revealed that oxidative DNA damage is one of the earliest detectable events during the progression from healthy aging to dementia. Moreover, the increase in DNA damage is paralleled by a decrease in DNA repair activities. Several hypotheses are currently tested in order to explain the decreased DNA repair activity observed in MCI and AD subjects. Some authors have suggested that mutations …or polymorphisms in DNA repair genes might impair DNA repair. However, this hypothesis does not seem to be confirmed by recent genetic association studies. Others suggest that DNA repair proteins might be inactivated by oxidative induced post-translational modifications or degradation. There is also indication that different isoforms of the same repair protein might be involved in the progression from early to late stages AD. Moreover, a widespread activation of DNA repair pathways might generate death signals ending with neuronal apoptosis. A link between environmental induced epigenetic modification, oxidation, and repair of AD related genes has been also proposed. Most of these studies have been performed during the last few years, and we are still at the beginning of understanding the complex interplay between oxidative DNA damage, DNA repair, and neuronal death in the brain leading to Alzheimer's dementia, making this topic an exciting and promising field for future investigation. Show more

Keywords: Alzheimer's disease, base excision repair, DNA repair, DNA damage, epigenetics, mild cognitive impairment, oxidative DNA damage

DOI: 10.3233/JAD-2010-1415

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 953-966, 2010

Authors: Mihaescu, Raluca | Detmar, Symone B. | Cornel, Martina C. | van der Flier, Wiesje M. | Heutink, Peter | Hol, Elly M. | Rikkert, Marcel G.M. Olde | van Duijn, Cornelia M. | Janssens, A. Cecile J.W.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most prevalent form of dementia and the number of cases is expected to increase exponentially worldwide. Three highly penetrant genes (AβPP, PSEN1, and PSEN2) explain only a small number of AD cases with a Mendelian transmission pattern. Many genes have been analyzed for association with non-Mendelian AD, but the only consistently replicated finding is APOE. At present, possibilities for prevention, early detection, and treatment of the disease are limited. Predictive and diagnostic genetic testing is available only in Mendelian forms of AD. Currently, APOE genotyping is not considered clinically useful for screening, presymptomatic testing, or …clinical diagnosis of non-Mendelian AD. However, clinical management of the disease is expected to benefit from the rapid pace of discoveries in the genomics of AD. Following a recently developed framework for the continuum of translation research that is needed to move genetic discoveries to health applications, this paper reviews recent genetic discoveries as well as translational research on genomic applications in the prevention, early detection, and treatment of AD. The four phases of translation research include: 1) translation of basic genomics research into a potential health care application; 2) evaluation of the application for the development of evidence-based guidelines; 3) evaluation of the implementation and use of the application in health care practice; and 4) evaluation of the achieved population health impact. Most research on genome-based applications in AD is still in the first phase of the translational research framework, which means that further research is still needed before their implementation can be considered. Show more

Keywords: Alzheimer's disease, genomics, review, translational research

DOI: 10.3233/JAD-2010-1410

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 967-980, 2010

Authors: Xia, Weiming

Article Type: Review Article

Abstract: The amyloid-β protein (Aβ)-containing neuritic plaques and hyperphosphorylated tau-containing neurofibrillary tangles are two invariable characteristics of Alzheimer's disease (AD). Three genes encoding amyloid-β protein precursor (AβPP), presenilin (PS) 1 and 2 are linked to early onset familial AD, and the apolipoprotein E (ApoE) ε4 allele is a major risk factor for sporadic AD. The zebrafish AβPP, PS, and ApoE genes have been identified, and the essential components of the γ-secretase complex that mediates cleavage of AβPP to generate Aβ have been examined in zebrafish. A transgenic zebrafish expressing mutant tau has been created, and the transgenic animals exhibit a neurodegeneration …phenotype. The use of zebrafish as a model system for AD research has expanded our knowledge of Aβ and tau. Show more

Keywords: Alzheimer, amyloid, secretase, tau, transgenic, zebrafish

DOI: 10.3233/JAD-2010-1412

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 981-990, 2010

Authors: Arosio, Beatrice | Viazzoli, Chiara | Mastronardi, Luigina | Bilotta, Claudio | Vergani, Carlo | Bergamaschini, Luigi

Article Type: Short Communication

Abstract: Adenosine suppresses immune responses through the adenosine A2A receptors (A2A R). We evaluated the expression of A2A R in blood mononuclear cells (PBMCs) of patients with mild cognitive impairment (MCI), Alzheimer's disease (AD), and controls in order to verify if it may help distinguish different forms of cognitive decline. There was a significant linear increase in both mRNA levels and receptor density from multiple cognitive domain MCI (mcd-MCI) to amnestic MCI (a-MCI), spanning through AD and controls, without any significant difference between the latter two groups of subjects. These data, which need to be confirmed in a larger number …of patients, suggest that expression of A2A R in PBMCs may be a valuable means of differentiating a-MCI and mcd-MCI. Show more

Keywords: Adenosine receptors, Alzheimer's disease, inflammation, mild cognitive impairment

DOI: 10.3233/JAD-2010-090814

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 991-996, 2010

Authors: Cavallaro, Rosaria A. | Fuso, Andrea | Nicolia, Vincenzina | Scarpa, Sigfrido

Article Type: Short Communication

Abstract: Oxidative stress, altered glutathione levels, and hyperhomocysteinemia play critical roles in Alzheimer's disease. We studied the relationships between hyperhomocysteinemia, glutathione, and oxidative stress in TgCRND8 mice maintained in conditions of folate, B12, and B6 deficiency and the effect of S-adenosylmethionine supplementation. We found that hyperhomocysteinemia was correlated with increased reduced/oxidized brain glutathione ratio, with decreased glutathione S-transferase activity and increased lipid peroxidation. S-adenosylmethionine potentiated superoxide dismutase and glutathione S-transferase activity and restored altered brain glutathione and erythrocytes lipid peroxidation. These results underline the importance of S-adenosylmethionine as neuroprotective compound, acting both on methylation and oxidation metabolism.

Keywords: Amyloid-β, glutathione, homocysteine, oxidative stress, S-adenosylmethionine

DOI: 10.3233/JAD-2010-091666

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 997-1002, 2010

Authors: Couch, Brian A. | DeMarco, George J. | Gourley, Shannon L. | Koleske, Anthony J.

Article Type: Short Communication

Abstract: Amyloid-β (Aβ) overproduction and dendrite arbor atrophy are hallmarks of Alzheimer's disease. The RhoA GTPase (Rho) signals through Rho kinase (ROCK) to control cytoskeletal dynamics and regulate neuron structure. Hyperactive Rho signaling destabilizes neurons leading to dendritic regression that can be rescued by genetic or pharmacological reduction of ROCK signaling. To understand what effect reduced ROCK signaling has on the dendrite arbors of mice that overproduce Aβ, we administered the ROCK inhibitor fasudil to AβPP/PS1 transgenic mice. We report that increased dendrite branching occurs in AβPP/PS1 mice and that fasudil promotes lengthening of the dendrite arbors of CA1 pyramidal neurons.

Keywords: Amyloid-β protein precursor, dendrites, fasudil, hippocampus, intracerebroventricular infusion, presenilin-1, Rho GTPase, Rho kinase

DOI: 10.3233/JAD-2010-091114

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1003-1008, 2010

Authors: Westmark, Cara J. | Westmark, Pamela R. | Malter, James S.

Article Type: Short Communication

Abstract: Amyloid-β protein precursor (AβPP) is overexpressed in Alzheimer's disease (AD), Down syndrome (DS), autism, and fragile X syndrome. Seizures are a common phenotype in all of these neurological disorders, yet the underlying molecular mechanism(s) of seizure induction and propagation remain largely unknown. We demonstrate that AD (Tg2576) and DS (Ts65Dn) mice exhibit audiogenic seizures, which can be attenuated with antagonists to metabotropic glutamate receptor 5 (mGluR5 ) or by passive immunization with anti-amyloid-β antibody. Our data strongly implicates AβPP or a catabolite in seizure susceptibility and suggests that mGluR5 mediates this response.

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, audiogenic seizure, Down syndrome, metabotropic glutamate receptor 5

DOI: 10.3233/JAD-2010-100087

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1009-1013, 2010

Authors: Aho, Leena | Pikkarainen, Maria | Hiltunen, Mikko | Leinonen, Ville | Alafuzoff, Irina

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), has been reported to be detected in the intracellular compartment. Most studies reporting the presence of intracellular Aβ are based on the use of immunohistochemistry. In this study, the presence of AβPP and Aβ was assessed by applying immunohistochemistry in postmortem human brain tissue samples obtained from 10 neurologically intact subjects, the youngest being 2 years of age, one aged with mild cognitive impairment, 14 neurologically diseased, and in one brain biopsy sample obtained from a subject with normal pressure hydrocephalus. Intracellular immunoreactivity was detected in all ages …independent of the disease state or existence of extracellular Aβ aggregates with all antibodies directed to AβPP, with three Aβ antibodies (4G8, 6E10, and 82E1), clones that are unable to distinguish Aβ from AβPP. These results suggest that it is AβPP rather than Aβ that is detected intracellularly when using the antibodies listed above. Furthermore, the staining results varied when different pretreatment strategies were applied. Interestingly intracellular Aβ was detected with antibodies directed to the C-terminus of Aβ (neoepitope) in subjects with Alzheimer's disease. The lack of intracellular immunoreactivity in unimpaired subjects, when using antibodies against neoepitopes, may be due to a lack or a low level of the protein that is thus undetectable at light microscopic level by immunohistochemistry method. The staining results and conclusions depended strongly on the chosen antibody and the pretreatment strategy and thus multiple antibodies must be used when assessing the intracellular accumulation of Aβ. Show more

Keywords: Amyloid-β, immunohistochemistry, intracellular, postmortem brain

DOI: 10.3233/JAD-2010-091681

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1015-1028, 2010

Authors: Mangialasche, Francesca | Kivipelto, Miia | Mecocci, Patrizia | Rizzuto, Debora | Palmer, Katie | Winblad, Bengt | Fratiglioni, Laura

Article Type: Research Article

Abstract: In this study we investigated the association between plasma levels of eight forms of vitamin E and incidence of Alzheimer's disease (AD) among oldest-old individuals in a population-based setting. A dementia-free sample of 232 subjects aged 80+ years, derived from the Kungsholmen Project, was followed-up to 6 years to detect incident AD. Plasma levels of vitamin E (α-, β-, γ, and δ-tocopherol; α-, β-, γ-, and δ-tocotrienol) were measured at baseline. Vitamin E forms-AD association was analyzed with Cox proportional hazard model after adjustment for several potential confounders. Subjects with plasma levels of total tocopherols, total tocotrienols, or total vitamin …E in the highest tertile had a reduced risk of developing AD in comparison to persons in the lowest tertile. Multi-adjusted hazard ratios (HRs) and 95% confidence interval (CI) were 0.55 (0.32–0.94) for total tocopherols, 0.46 (0.23–0.92) for total tocotrienols, and 0.55 (0.32–0.94) for total vitamin E. When considering each vitamin E form, the risk of developing AD was reduced only in association with high plasma levels of β-tocopherol (HR: 0.62, 95% CI 0.39–0.99), whereas α-tocopherol, α- tocotrienol, and β-tocotrienol showed only a marginally significant effect in the multiadjusted model [HR (95% CI): α-tocopherol: 0.72 (0.48–1.09); α-tocotrienol: 0.70 (0.44–1.11); β-tocotrienol: 0.69 (0.45–1.06)]. In conclusion, high plasma levels of vitamin E are associated with a reduced risk of AD in advanced age. The neuroprotective effect of vitamin E seems to be related to the combination of different forms, rather than to α-tocopherol alone, whose efficacy in interventions against AD is currently debated. Show more

Keywords: Alzheimer's disease, elderly, oxidative stress, tocopherol, tocotrienol, vitamin E

DOI: 10.3233/JAD-2010-091450

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1029-1037, 2010

Authors: Mattsson, Niklas | Johansson, Per | Hansson, Oskar | Wallin, Anders | Johansson, Jan-Ove | Andreasson, Ulf | Andersen, Oluf | Haghighi, Sara | Olsson, Maria | Stridsberg, Mats | Svensson, Johan | Blennow, Kaj | Zetterberg, Henrik

Article Type: Research Article

Abstract: Much is unknown regarding the regulation of Alzheimer-related amyloid-β protein precursor (AβPP)-processing in the human central nervous system. It has been hypothesized that amyloidogenic AβPP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of AβPP-derived molecules in cerebrospinal fluid (CSF) with chromogranin (Cg) derived peptides, representing the regulated secretion. Patients with Alzheimer's disease (AD, N=32), multiple sclerosis (MS, N=50), and healthy controls (N= 70) were enrolled. CSF was analyzed for the amyloid peptides Aβ1-42 , Aβx-42 , Aβx-40 , Aβx-38 , α-cleaved soluble AβPP (sAβPPα), β-cleaved soluble AβPP (sAβPPβ), and peptides …derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes AβPP into Aβ, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. CSF Cg levels correlated to sAβPP and Aβ peptides in AD, MS, and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. These results suggest that a large part of AβPP in the human central nervous system is processed in the regulated secretory pathway of neurons. Show more

Keywords: Amyloid, BACE1, chromogranin, metabolism, regulated secretory pathway

DOI: 10.3233/JAD-2010-091651

Citation: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1039-1049, 2010