Journal of Alzheimer's Disease - Volume 18, issue 4

Authors: Salkovic-Petrisic, Melita | Osmanovic, Jelena | Grünblatt, Edna | Riederer, Peter | Hoyer, Siegfried

Article Type: Review Article

Abstract: Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-β protein precursor derivatives amyloid-β (Aβ)1-40 and Aβ1-42/43 lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Aβ as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing diseases that only becoming manifest late in life. With aging, …a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Aβ as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review. Show more

Keywords: Amyloid-β, brain, hyperphosphorylated tau, insulin, insulin resistant brain state, oxidative metabolism, sporadic Alzheimer disease

DOI: 10.3233/JAD-2009-1184

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 729-750, 2009

Authors: Antúnez, Carmen | Boada, Mercé | López-Arrieta, Jesús | Ramirez-Lorca, Reposo | Hernández, Isabel | Marín, Juan | Martínez-Lage, Pablo | González-Pérez, Antonio | Jorge Galan, José | Gayán, Javier | Real, Luis M. | Ruiz, Agustín

Article Type: Short Communication

Abstract: GOLPH2 gene SNP variants Rs10868366 and Rs7019241 were reported to decrease the risk of Alzheimer's disease in a recent Whole Genome Association Study. We have investigated these genetic variants in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP markers. We found no evidence of association between GOLPH2 markers and susceptibility to Alzheimer's disease in our series. We concluded that GOLPH2 gene does not contribute to risk of disease in this study sample.

Keywords: Alzheimer's disease, complex diseases, genetic susceptibility, Genome Wide Association Studies (GWAS), GOLPH2, human molecular genetics, neurodegeneration

DOI: 10.3233/JAD-2009-1200

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 751-754, 2009

Authors: Moreno-Gonzalez, Ines | Baglietto-Vargas, David | Sanchez-Varo, Raquel | Jimenez, Sebastian | Trujillo-Estrada, Laura | Sanchez-Mejias, Elisabeth | del Rio, Juan Carlos | Torres, Manuel | Romero-Acebal, Manuel | Ruano, Diego | Vizuete, Marisa | Vitorica, Javier | Gutierrez, Antonia

Article Type: Research Article

Abstract: Here we demonstrated that extracellular, not intracellular, amyloid-β (Aβ) and the associated cytotoxic glial neuroinflammatory response are major contributors to early neuronal loss in a PS1xAPP model. A significant loss of principal (27%) and SOM/NPY (56–46%) neurons was found in the entorhinal cortex at 6 months of age. Loss of principal cells occurred selectively in deep layers (primarily layer V) whereas SOM/NPY cell loss was evenly distributed along the cortical column. Neither layer V pyramidal neurons nor SOM/NPY interneurons displayed intracellular Aβ immunoreactivity, even after formic acid retrieval; thus, extracellular factors should be preferentially implicated in this selective neurodegeneration. Amyloid …deposits were mainly concentrated in deep layers at 4–6 months, and of relevance was the existence of a potentially cytotoxic inflammatory response (TNFα, TRAIL, and iNOS mRNAs were upregulated). Moreover, non-plaque associated activated microglial cells and reactive astrocytes expressed TNFα and iNOS, respectively. At this age, in the hippocampus of same animals, extracellular Aβ induced a non-cytotoxic glial activation. The opposite glial activation, at the same chronological age, in entorhinal cortex and hippocampus strongly support different mechanisms of disease progression in these two regions highly affected by Aβ pathology. Show more

Keywords: Alzheimer's disease, amyloid, entorhinal cortex, microglia, neurodegeneration, neuroinflammation, transgenic

DOI: 10.3233/JAD-2009-1192

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 755-776, 2009

Authors: Loskutova, Natalia | Honea, Robyn A. | Vidoni, Eric D. | Brooks, William M. | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Studies suggest a link between bone loss and Alzheimer's disease. To examine bone mineral density (BMD) in early Alzheimer's disease (AD) and its relationship to brain structure and cognition, we evaluated 71 patients with early stage AD (Clinical Dementia Rating (CDR) 0.5 and 1) and 69 non-demented elderly control participants (CDR 0). Measures included whole body BMD by dual energy x-ray absorptiometry (DXA) and normalized whole brain volumes computed from structural MRI scans. Cognition was assessed with a standard neuropsychological test battery. Mean BMD was lower in the early AD group (1.11 ± 0.13) compared to the non-demented control group …(1.16 ± 0.12, p = 0.02), independent of age, gender, habitual physical activity, smoking, depression, estrogen replacement, and apolipoprotein E4 carrier status. In the early AD group, BMD was related to whole brain volume (b = 0.18, p = 0.03). BMD was also associated with cognitive performance, primarily in tests of memory (logical memory [b = 0.15, p = 0.04], delayed logical memory [b = 0.16, p = 0.02], and the selective reminding task – free recall [b = 0.18, p = 0.009]). BMD is reduced in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early AD. Show more

Keywords: Alzheimer's disease, bone mineral density, brain atrophy, hypothalamus, memory

DOI: 10.3233/JAD-2009-1185

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 777-785, 2009

Authors: Tchantchou, Flaubert | Lacor, Pascale N. | Cao, Zhiming | Lao, Lixing | Hou, Yan | Cui, Changhai | Klein, William L. | Luo, Yuan

Article Type: Research Article

Abstract: Loss of synapses has been correlated with dementia in Alzheimer's disease (AD) as an early event during the disease progression. Hence, synaptogenesis and neurogenesis in adulthood could serve as a therapeutic target for the prevention and treatment of AD. Recently, we have demonstrated enhanced hippocampal neurogenesis by oral administration of Ginkgo biloba extract (EGb 761) to a mouse model of AD. This study aims to identify the constituents that contribute to EGb 761-induced neurogenesis. Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of …cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-β oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation. Show more

Keywords: Amyloid-beta derived diffusible ligands (ADDL), bilobalide, CREB, neurogenesis, quercetin, synaptogenesis

DOI: 10.3233/JAD-2009-1189

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 787-798, 2009

Authors: Yang, Xiao-Hui | Huang, Han-Chang | Chen, Lin | Xu, Wei | Jiang, Zhao-Feng

Article Type: Research Article

Abstract: Cu(II) has been shown in vitro to profoundly promote the aggregation of amyloid-β peptide (Aβ, a key pathological event in Alzheimer's disease. We investigated both the effect of Cu(II) on the secondary structure transformation of Aβ and the probable residues involved in the chelation to Cu(II). The effects of Cu(II) on Aβ was analyzed by the circular dichroism spectra, Th-T fluorescence and sedimentation assay, and the results indicated that Cu(II) could disrupt the already formed β-sheet structure, convert β-sheeted aggregates into non-β-sheeted aggregates and promote oligomeric Aβ to precipitate in a non-β-sheeted aggregation way. Additionally, we confirmed that the function …of Cu(II) discussed above was achieved through its interaction with His6, His13, and His14 by investigating an Aβ mutant, 23,6,13,14 Aβ1-40 . Show more

Keywords: Alzheimer's disease, amyloid-β peptide, β-sheet structure, copper

DOI: 10.3233/JAD-2009-1186

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 799-810, 2009

Authors: House, Emily | Mold, Matthew | Collingwood, Joanna | Baldwin, Alex | Goodwin, Steven | Exley, Christopher

Article Type: Research Article

Abstract: The observation of the co-deposition of metals and amyloid-β42 (Aβ42 ) in brain tissue in Alzheimer's disease prompted myriad investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric Aβ42 and upon precipitation of the copper-peptide complex thereby prevents Aβ42 from adopting a β-sheet secondary structure. Copper is also bound by β-sheet conformers of Aβ42 , and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar Aβ42 with, for example, a 20-fold excess …of the metal resulting in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of Aβ42 . The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer's disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the β-sheet secondary structure of pre-formed, aged amyloid fibrils of Aβ42 . Copper may protect against the presence of β-sheets of Aβ42 in vivo, and its binding by fibrillar Aβ42 could have implications for Alzheimer's disease therapy. Show more

Keywords: Aluminum, Alzheimer's disease, amyloid, Aβ42, β-sheet, Congo red, copper, spherulites, TEM, thioflavin T

DOI: 10.3233/JAD-2009-1235

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 811-817, 2009

Authors: Popp, Julius | Lewczuk, Piotr | Linnebank, Michael | Cvetanovska, Gabriela | Smulders, Yvo | Kölsch, Heike | Frommann, Ingo | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank

Article Type: Research Article

Abstract: Disturbed homocysteine metabolism is a risk factor for Alzheimer's disease (AD) and may contribute to the disease pathophysiology by increasing both amyloid-β (Aβ) production and phosphorylated tau (P-tau) accumulation. Here, we evaluated the relationship between the cerebrospinal fluid (CSF) concentrations of homocysteine (Hcys), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and 5-methyltetrahydrofolate (5-MTHF), and the markers for AD pathology, Aβ1-42 and P-tau181, in 98 cognitively healthy subjects aged 16-81 years and 54 AD patients. In multivariate regression tests including age, gender, creatinine, and presence of the apolipoprotein E ε4 allele, P-tau181 was associated with SAH (β = 0.490; p < 0.001), 5-MTHF …(β = -0.273; p = 0.010) levels, and SAM/SAH ratio (β = -0.319; p = 0.013) in controls, and with SAH (β = 0.529; p = 0.001) in AD patients. The levels of Aβ1-42 were not associated with the CSF concentrations of Hcys, SAM, SAH, or 5-MTHF neither in the AD nor in the control group. The results suggest that alteration of the homocysteine metabolism is related to increased accumulation of phosphorylated tau and may contribute to the neurofibrillary pathology in normal aging and in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, homocysteine, phosphorylated tau

DOI: 10.3233/JAD-2009-1187

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 819-828, 2009

Authors: Pani, Alessandra | Dessì, Sandra | Diaz, Giacomo | La Colla, Paolo | Abete, Claudia | Mulas, Claudia | Angius, Fabrizio | Cannas, Maria D. | Orru, Christina D. | Cocco, Pier Luigi | Mandas, Antonella | Putzu, Paolo | Laurenzana, Anna | Cellai, Cristina | Costanza, Antonio Mitidieri | Bavazzano, Antonio | Mocali, Alessandra | Paoletti, Francesco

Article Type: Research Article

Abstract: Intracellular cholesterol metabolism was reported to modulate amyloid-β (Aβ) generation in Alzheimer's disease (AD). Results presented herein demonstrated that, like brain cells, cultured skin fibroblasts from AD patients contained more cholesterol esters than fibroblasts from healthy subjects. Particularly, Oil Red-O, Nile Red, and filipin staining highlighted higher levels of neutral lipids which responded to inhibitors of acyl-coenzyme A:cholesterol acyl-transferase (ACAT-1), associated with an increase in free cholesterol. ACAT-1 mRNA levels increased significantly in AD fibroblasts, whereas those of sterol regulatory element binding protein-2, neutral cholesterol ester hydrolase, and ATP-binding cassette transporter member 1 were markedly down-regulated. Instead, mRNA levels of …low-density lipoprotein receptor, hydroxy-methyl-glutaryl-coenzyme A reductase, caveolin-1, and amyloid-β protein precursor (AβPP) were virtually unchanged. Notably, mRNA levels of both β-site AβPP-cleaving enzyme 1 (BACE1) and neprilysin were significantly down-regulated. An increase in Aβ40 ; and Aβ42 ; immunostaining and a decrease in BACE1 active form were also found in AD versus control fibroblasts. Altogether, these findings support the hypothesis that the derangement of cholesterol homeostasis is a systemic alteration involving central but also peripheral cells of AD patients, and point to cholesterol ester levels in AD fibroblasts as an additional metabolic hallmark useful in the laboratory and clinical practice. Show more

Keywords: ACAT-1, Alzheimer's disease (AD), cholesterol homeostasis, cholesterol esterification, filipin, human fibroblasts, lipids, Nile Red, Oil Red-O, peripheral AD markers

DOI: 10.3233/JAD-2009-1193

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 829-841, 2009

Authors: Goñi-Oliver, Paloma | Avila, Jesús | Hernández, Félix

Article Type: Research Article

Abstract: Deregulation of glycogen synthase kinase-3 (GSK-3) activity is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). GSK-3 activity is regulated by phosphorylation and through interaction with GSK-3-binding proteins. Previously, we demonstrated that calpain activation produces a truncation of GSK-3. In this study, we show that calpain-mediated GSK-3 truncation, induced by N-methyl-D-aspartic acid (NMDA), depends on extracellular calcium. Primary cultures of cortical neurons treated with NMDA reduce GSK-3 levels up to 75%, although the truncated form of GSK-3 does not accumulate, suggesting that a short-lived product is formed. The data obtained with human AD samples suggest …that, although a great variability exists at least in postmortem samples, truncated GSK-3 does not accumulate. However, memantine, a non-competitive NMDA receptor which has been approved for the treatment of moderate to severe AD, is able to inhibit GSK-3 truncation induced by NMDA in primary cultures of cortical neurons in a dose-dependent manner. Thus, memantine modulates GSK-3 signaling, which might explain its protective role in AD. Overall, our data reinforces the important relationship between NMDA receptors and GSK-3 and their involvement as one of the first steps in neurodegenerative diseases such as AD. Show more

Keywords: Alzheimer's disease, calpain, glycogen synthase kinase-3 (GSK-3), N-methyl-D-aspartic acid (NMDA), proteolysis

DOI: 10.3233/JAD-2009-1190

Citation: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 843-848, 2009