Journal of Alzheimer's Disease - Volume 13, issue 2

Authors: Dolga, Amalia M. | Nijholt, Ingrid M. | Ostroveanu, Anghelus | ten Bosch, Quirine | Luiten, Paul G.M. | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Statins are widely used as medication to lower cholesterol levels in human patients. In addition, it was recently reported that they also reduce the incidence of stroke and progression of Alzheimer's disease when prophylactically administered. To date there is only limited information available on how statins exert this beneficial effect. In this study we investigated the neuroprotective effect of lovastatin in primary cortical neurons. We found that lovastatin protects cortical neurons in a concentration-dependent manner against glutamate-mediated excitotoxicity. Interestingly, lovastatin with or without glutamate and/or tumor necrosis factor-alpha (TNF-α) increased TNF receptor 2 (TNF-R2) expression in cortical neurons. It was …previously shown that activation of TNF-R2 signaling, which includes phosphorylation of protein kinase B (PKB)/Akt and activation of nuclear factor-kappa B (NF-κB), protects neurons against ischemic or excitotoxic insults. To investigate if lovastatin-induced neuroprotection was mediated by TNF-R2 signaling, primary cortical neurons were isolated from TNF-R1-/- or TNF-R2-/- mice. We could show that lovastatin is neuroprotective in TNF-R1-/- neurons, while protection is completely absent in TNF-R2-/- neurons. Furthermore, lovastatin-mediated neuroprotection led to an increase in PKB/Akt and NF-κB phosphorylation, whereas inhibition of PKB/Akt activation entirely abolished lovastatin-induced neuroprotection. Thus, lovastatin-induced neuroprotection against glutamate-excitotoxicity via activation of TNF-R2-signaling pathways. Show more

Keywords: excitotoxicity, neuronal culture, NF-κB, PKB/Akt, statin

DOI: 10.3233/JAD-2008-13201

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 111-122, 2008

Authors: Willis, Michael | Prokesch, Manuela | Hutter-Paier, Birgit | Windisch, Manfred | Stridsberg, Mats | Mahata, Sushil K. | Kirchmair, Rudolf | Wietzorrek, Georg | Knaus, Hans-Günther | Jellinger, Kurt | Humpel, Christian | Marksteiner, Josef

Article Type: Research Article

Abstract: Chromogranin B and secretogranin II are major soluble constituents of large dense core vesicles of presynaptic structures and have been found in neuritic plaques of Alzheimer patients. We examined the distribution and expression of these peptides in both transgenic mice over expressing human amyloid-β protein precursor APP751 with the London (V717I) and Swedish (K670M/N671L) mutations and in human post-mortem brain. In transgenic mice, the number of amyloid-β plaques and chromogranin immunopositive plaques increased from 6 to 12 months. About 60% of amyloid-β plaques were associated with chromogranin B and about 40% with secretogranin II. Chromogranin immunoreactivity appeared mainly …as swollen dystrophic neurites. Neither synaptophysin- nor glial fibrillary acidic protein- immunoreactivity was expressed in chromogranin immunoreactive structures at any timepoint. Density of chromogranin peptides in hippocampal structures did not change in transgenic animals at any timepoint, even though animals had a poorer performance in the Morris water maze task. In conclusion, our findings in transgenic animals partly resembled findings in Alzheimer patients. Chromogranin peptides were associated with amyloid-β plaques, but were not reduced in specific brain areas as previously reported by our group. Therefore specific changes of chromogranin peptides observed in Alzheimer patients can be related to amyloid-β pathology only. Show more

Keywords: Alphabetize: amyloid-beta, chromogranin B, large dense core vesicles, secretogranin II, transgenic

DOI: 10.3233/JAD-2008-13202

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 123-135, 2008

Authors: Rimajova, Mira | Lenzo, Nat P. | Wu, Jing-Shan | Bates, Kristyn A. | Campbell, Andrew | Dhaliwal, Satvinder S. | McCarthy, Michael | Rodrigues, Mark | Paton, Athena | Rowe, Christopher | Foster, Jonathan K. | Martins, Ralph N.

Article Type: Research Article

Abstract: Apolipoprotein E-ϵ4 (APOEε4) has been associated with increased risk of developing Alzheimer's disease (AD) and regional cerebral glucose hypometabolism, as measured by fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET). We report here preliminary data from studies that aim to determine whether cerebral glucose hypometabolism is observed in APOEε4 positive, cognitively intact individuals between the ages of 50 and 80, and whether there is an additional impact of subjective memory complainer (SMC) status on glucose metabolism determined by NeuroStat analysis. FDG-PET was conducted in 30 community dwelling, APOE-ε4 carriers without clinical evidence of dementia and objective cognitive impairment as assessed using a neuropsychological battery. …Neurological soft-signs (NSS) were also assessed. Glucose hypometabolism was demonstrated in the anterior and posterior cingulate cortex and in the temporal association cortices in APOEε4 carriers compared to the normative NeuroStat database. This pattern was particularly evident in APOEε4 heterozygous individuals. SMC showed hypometabolism in the aforementioned brain regions, whereas non-SMC showed no significant pattern of glucose hypometabolism. FDG-PET with NeuroStat analysis showed that APOEε4 carriers have mild glucose hypometabolism in areas associated with AD. SMC may be associated with AD-related differences in regional cerebral glucose metabolism. These findings are currently being investigated in a larger group of APOEε4 carriers. Show more

Keywords: Alzheimer's disease, apolipoprotein E, cognitive aging, FDG-PET, memory

DOI: 10.3233/JAD-2008-13203

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 137-146, 2008

Authors: Bharadwaj, Prashant | Waddington, Lynne | Varghese, Jose | Macreadie, Ian G.

Article Type: Short Communication

Abstract: The 42 amino acid amyloid-β (Aβ) can exist in multiple physical states including oligomers and fibrils. This study shows that fibril formation is hastened by the biological buffers required to support the growth of mammalian cells, but is prevented if Aβ is maintained in water. Here we describe a method to produce Aβ in oligomeric form and the comparison of stable fibrillar and non-fibrillar forms in cell toxicity studies in water, achieved through the use of yeast. We show that extracellular, non-fibrillar Aβ causes a dose dependent loss of cell viability while fibrillar Aβ has low toxicity.

DOI: 10.3233/JAD-2008-13204

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 147-150, 2008

Authors: Gentile, Antonietta | Amadoro, Giuseppina | Corsetti, Veronica | Ciotti, Maria T. | Serafino, AnnaLucia | Calissano, Pietro

Article Type: Research Article

Abstract: The precursor of the non-amyloid-β component of Alzheimer's disease amyloid (NACP), also known as α-synuclein, is a presynaptic terminal molecule that accumulates in the senile plaques of Alzheimer's disease. Aberrant accumulation of this protein into insoluble aggregates has also been implicated in the pathogenesis of many other neurodegenerative diseases, collectively referred to as synucleinopathies. However, the precise pathogenetic mechanism that leads to aggregate formation and the consequent cellular damage remains elusive. Analyzing differentiated primary cultures of cerebellar granule neurons undergoing apoptosis due to K+ reduction from 25 mM to 5.0 mM, a neuronal model widely used to study event linking …apoptosis and neurodegeneration [1], we assessed that endogenous monomeric α-synuclein decreases and spontaneously aggregates into detergent-insoluble high molecular species. Apoptosis is also correlated with a marked redistribution/accumulation of this protein from terminal neurites to perikaria, with formation of compact inclusion bodies in juxta-nuclear area. In addition, secretion of monomeric α-synuclein decreases in response to apoptotic stimulus, while part of it aggregates into fibrillar structures and becomes detectable by immunogold-electron microscope analysis. The data presented in this study demonstrate that an apoptotic event caused by a “physiological” trigger, such as neuronal membrane repolarization of cultured cerebellar granule neurons, induces α-synuclein intracellular redistribution and aggregation, two molecular events reminiscent of those occurring in different human neurodegenerative diseases all characterized by α-synuclein-positive inclusions. Our study indicates this in vitro neuronal system as an excellent model to dissect pathogenic mechanism(s). Show more

Keywords: α-synuclein, aggregation, apoptosis, CGNs

DOI: 10.3233/JAD-2008-13205

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 151-160, 2008

Authors: Guerrero, Rosa | Navarro, Paloma | Gallego, Eva | Avila, Jesus | de Yebenes, Justo G. | Sanchez, Marina P.

Article Type: Research Article

Abstract: Mutations, haplotypes, and polymorphisms of tau and Park-2 genes constitute risk factors for developing tauopathies. In order to analyze the possible relationship between parkin and tau we generated a double-mutant mouse deficient for Park-2 expression and overexpressing a mutant tau protein (hTauVLW). Mice develop normally, although the median survival rate is considerably reduced with respect to wild type (45%). Aggregates of phosphorylated tau in neurons and reactive gliosis are quite abundant in cortex and hippocampus of these mice. Moreover, while in young transgenic mice the hTauVLW immunostained transgene product is observed in both cell bodies and dendrites, the hTauVLW mutant …protein is only detected in the neuronal cell bodies when Park-2 gene is additionally deleted. Moreover, DNA fragmentation was detected by the TUNEL method, and cerebral atrophy is also present in these regions. The levels of phosphorylated tau and Hsp70 are increased in the double-mutant mice, while CHIP expression in hippocampus is lower when the Park-2 gene is deleted. Thus, the combination of Park-2 gene deletion with hTauVLW transgene overexpression in mice produces serious neuropathological effects, which reflect the existence of some relationship between both proteins. Show more

Keywords: FTDP-17 tau mutations, neurodegeneration, Park-2 gene deletion, parkin ubiquitin ligase, tau hyperphosphorylation

DOI: 10.3233/JAD-2008-13206

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 161-172, 2008

Authors: Silva, Patrícia Natália Oliveira | Gigek, Carolina Oliveira | Leal, Mariana Ferreira | Bertolucci, Paulo Henrique Ferreira | de Labio, Roger Willian | Payão, Spencer Luiz Marques | Smith, Marília de Arruda Cardoso

Article Type: Short Communication

Abstract: Longevity related genes were investigated concerning promoter methylation. SIRT3, SMARCA5, HTERT and CDH1 promoters were analyzed in peripheral blood in relation to gender, age and Alzheimer's disease (AD). Methylation Specifc PCR assay (MSP) was used. There were no significant differences in methylation frequencies of SIRT3, SMARCA5 and CDH1 among young, elderly and AD groups (p> 0.05), showing no association with aging or AD. On the other hand, HTERT methylation frequency was associated with the aging process, in that AD patients differed from elderly controls (p=0.0086), probably due to telomere and immune dysfunctions involved in AD pathogenesis.

Keywords: Aging, Alzheimer's disease, CDH1, DNA methylation, epigenetics, HTERT, SIRT3, SMARCA5

DOI: 10.3233/JAD-2008-13207

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 173-176, 2008

Authors: Santa-Maria, Ismael | Cuadros, Raquel | Moreno, Francisco J. | Muñoz, Victor | Ávila, Jesús | Hernández, Félix

Article Type: Research Article

Abstract: Human recombinant tau can bind to the end of isolated human paired helical filaments (PHF). The sequential binding of tau protein to PHF could result in an elongation of the previously polymerized PHF. However, we have observed that the elongation takes place in a different way on different types of PHF. We have found that there are at least three populations of PHF. For one population, tau protein is able to bind to the ends of the filament and to elongate that filament. In the second PHF population, tau protein binds but does not elongates the filament. In the third, …neither tau binding nor elongation was observed. Show more

Keywords: Elongation, paired helical filaments, tau protein

DOI: 10.3233/JAD-2008-13208

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 177-185, 2008

Authors: Carlsson, Cynthia M. | Gleason, Carey E. | Hess, Timothy M. | Moreland, Kimberly A. | Blazel, Hanna M. | Koscik, Rebecca L. | Schreiber, Nathan T.N. | Johnson, Sterling C. | Atwood, Craig S. | Puglielli, Luigi | Hermann, Bruce P. | McBride, Patrick E. | Stein, James H. | Sager, Mark A. | Asthana, Sanjay

Article Type: Research Article

Abstract: Background: Statins reduce amyloid-β (Aβ) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Aβ metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. Methods: In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Aβ42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. Results: Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Aβ42 …(p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. Conclusion: In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Aβ42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Aβ metabolism, but also other preclinical processes related to the development of AD. Show more

Keywords: Alzheimer's disease, amyloid β-protein, biological markers, cerebrospinal fluid, genetic predisposition to disease, hydroxymethylglutaryl-CoA reductase inhibitors, neuropsychological tests, simvastatin, tau proteins

DOI: 10.3233/JAD-2008-13209

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 187-197, 2008

Authors: Nazem, Amir | Mansoori, G. Ali

Article Type: Research Article

Abstract: A century of research has passed since the discovery and definition of Alzheimer's disease (AD), the primary common dementing disorder worldwide. However, AD lacks definite diagnostic approaches and effective cure at the present. Moreover, the currently available diagnostic tools are not sufficient for an early screening of AD in order to start preventive approaches. Recently the emerging field of nanotechnology has promised new techniques to solve some of the AD challenges. Nanotechnology refers to the techniques of designing and manufacturing nanosize (1–100 nm) structures through controlled positional and/or self-assembly of atoms and molecules. In this report, we present the promises …that nanotechnology brings in research on the AD diagnosis and therapy. They include its potential for the better understanding of the AD root cause molecular mechanisms, AD's early diagnoses, and effective treatment. The advances in AD research offered by the atomic force microscopy, single molecule fluorescence microscopy and NanoSIMS microscopy are examined here. In addition, the recently proposed applications of nanotechnology for the early diagnosis of AD including bio-barcode assay, localized surface plasmon resonance nanosensor, quantum dot and nanomechanical cantilever arrays are analyzed. Applications of nanotechnology in AD therapy including neuroprotections against oxidative stress and anti-amyloid therapeutics, neuroregeneration and drug delivery beyond the blood brain barrier (BBB) are discussed and analyzed. All of these applications could improve the treatment approach of AD and other neurodegenerative diseases. The complete cure of AD may become feasible by a combination of nanotechnology and some other novel approaches, like stem cell technology. Show more

Keywords: Alzheimer's disease, nanotechnology, amyloid, tau protein, atomic force microscopy, nanodiagnostics, targeted drug delivery

DOI: 10.3233/JAD-2008-13210

Citation: Journal of Alzheimer's Disease, vol. 13, no. 2, pp. 199-223, 2008