Journal of Alzheimer's Disease - Volume 10, issue 1

Authors: Zhang, Laura | Fiala, Milan | Cashman, John | Sayre, James | Espinosa, Araceli | Mahanian, Michelle | Zaghi, Justin | Badmaev, Vladimir | Graves, Michael C. | Bernard, George | Rosenthal, Mark

Article Type: Research Article

Abstract: Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-β (1-42) (Aβ) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Aβ plaques [5]. The natural product curcuminoids enhanced brain clearance of Aβ in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Aβ uptake using fluorescence and confocal microscopy. At baseline, the intensity of Aβ uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. …After treatment of macrophages with curcuminoids, Aβ uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain. Show more

Keywords: Alzheimer's disease, amyloid-β, phagocytosis, curcuminoids, immunomodulation

DOI: 10.3233/JAD-2006-10101

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 1-7, 2006

Authors: Tweedie, David | Brossi, Arnold | Chen, DeMoa | Ge, Yuan-Wen | Bailey, Jason | Yu, Qian-sheng | Kamal, Mohammad A. | Sambamurti, Kumar | Lahiri, Debomoy K. | Greig, Nigel H.

Article Type: Research Article

Abstract: Classical hallmarks of Alzheimer's disease (AD) are a synaptic loss, cholinergic neuron death, and abnormal protein deposition, particularly of toxic amyloid-β peptide (Aβ) that is derived from amyloid-β protein precursor (AβPP) by the action of beta- and gamma-secretases. The trigger(s) initiating the biochemical cascades that underpin these hallmarks have yet to be fully elucidated. The typical forebrain cholinergic cell demise associated with AD brain results in a loss of presynaptic cholinergic markers and acetylcholine (ACh). Neurine (vinyl-trimethyl-ammonium hydroxide) is a breakdown product of ACh, consequent to autolysis and is an organic poison found in cadavre brain. The time- and concentration-dependent …actions of neurine were assessed in human neuroblastoma (NB, SK-N-SH) cells in culture by quantifying cell viability by lactate dehydrogenase (LDH) and MTS assay, and AβPP and Aβ levels by Western blot and ELISA. NB cells displayed evidence of toxicity to neurine at ⩾ 3 mg/ml, as demonstrated by elevated LDH levels in the culture media and a reduced cell viability shown by the MTS assay. Using subtoxic concentrations of neurine, elevations in AβPP and Aβ1-40 peptide levels were detected in conditioned media samples. Show more

Keywords: Alzheimer's disease, neurine, amyloid-β protein precursor, amyloid-β peptide, acetylcholine, ptomaine

DOI: 10.3233/JAD-2006-10102

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 9-16, 2006

Authors: Exley, Christopher | Korchazhkina, Olga | Job, Deborah | Strekopytov, Stanislav | Polwart, Anthony | Crome, Peter

Article Type: Research Article

Abstract: There are unexplained links between human exposure to aluminium and the incidence, progression and aetiology of Alzheimer's disease. The null hypothesis which underlies any link is that there would be no Alzheimer's disease in the effective absence of a body burden of aluminium. To test this the latter would have to be reduced to and retained at a level that was commensurate with an Alzheimer's disease-free population. In the absence of recent human interference in the biogeochemical cycle of aluminium the reaction of silicic acid with aluminium has acted as a geochemical control of the biological availability of aluminium. This …same mechanism might now be applied to both the removal of aluminium from the body and the reduced entry of aluminium into the body while ensuring that essential metals, such as iron, are unaffected. Based upon the premise that urinary aluminium is the best non-invasive estimate of body burden of aluminium patients with Alzheimer's disease were asked to drink 1.5 L of a silicic acid-rich mineral water each day for five days and, by comparison of their urinary excretion of aluminium pre-and post this simple procedure, the influence upon their body burden of aluminium was determined. Drinking the mineral water increased significantly (P<0.001) their urinary excretion of silicic acid (34.3 ± 15.2 to 55.7 ± 14.2 μmol/mmol creatinine) and concomitantly reduced significantly P=0.037) their urinary excretion of aluminium (86.0 ± 24.3 to 62.2 ± 23.2 nmol/mmol creatinine). The latter was achieved without any significant (P>0.05) influence upon the urinary excretion of iron (20.7 ± 9.5 to 21.7 ± 13.8 nmol/mmol creatinine). The reduction in urinary aluminium supported the future longer-term use of silicic acid as non-invasive therapy for reducing the body burden of aluminium in Alzheimer's disease. Show more

Keywords: Alzheimer's disease, aluminium, silicic acid, iron, urinary excretion, mineral water, disease therapy

DOI: 10.3233/JAD-2006-10103

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 17-24, 2006

Authors: Savory, John | Herman, Mary M. | Ghribi, Othman

Article Type: Article Commentary

DOI: 10.3233/JAD-2006-10104

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 25-27, 2006

Authors: Dalton, Arthur J.

Article Type: Article Commentary

DOI: 10.3233/JAD-2006-10105

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 29-31, 2006

Authors: Zatta, Paolo

Article Type: Article Commentary

DOI: 10.3233/JAD-2006-10106

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 33-37, 2006

Authors: Miu, Andrei C.

Article Type: Article Commentary

DOI: 10.3233/JAD-2006-10107

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 39-42, 2006

Authors: Kamal, Mohammad A. | Klein, Peter | Yu, Qian-sheng | Tweedie, David | Li, Yazhou | Holloway, Harold W. | Greig, Nigel H.

Article Type: Research Article

Abstract: An explosion in the incidence of neurodegenerative diseases, particularly Alzheimer's disease (AD), is predicted in coming decades. Hence, the need to devise and assess new treatment strategies has never been more acute. AD, although an irreversible and progressive disorder, is currently treated with palliative, symptomatic therapy: primarily with acetylcholinesterase (AChE) inhibitors to amplify remaining cholinergic activity. New agents that, additionally, affect disease progression are sorely needed. Inhibition of brain butyrylcholinesterase (BuChE) represents a new drug target for AD treatment. Therefore, hand-in-hand with the development of selective ligands to inhibit BuChE in brain, it is fundamental to optimize assay conditions for …kinetic studies of human BuChE. Kinetic analysis of serum BuChE, which is structurally similar to brain enzyme, was performed at dual substrate (butyrylthiocholine iodide) concentration ranges: 3–80 μM (low) and 25–800 μM (optimal) by use of the Ellman technique. Interaction of BuChE with a novel experimental AD therapeutic, bisnorcymserine (BNC; 0.06–2.0 nM) was also studied ex vivo. The IC50 and other key kinetic constants were determined for human serum BuChE inhibition by BNC, which proved to be a highly potent inhibitor in comparison to its structural analogue, cymserine. BNC may, additionally, lower the amyloid plaque-associated protein, amyloid-β peptide. In synopsis, the characterization of the kinetic parameters of BuChE and BNC, described herein, is both aiding in the design of novel agents and optimizing their translation toward clinical use. Show more

Keywords: Alzheimer's disease, bisnorcymserine, butyrylcholinesterase, acetylcholinesterase, anticholinesterases, enzyme kinetics, phenserine, physostigmine, cholinergic

DOI: 10.3233/JAD-2006-10108

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 43-51, 2006

Authors: Pereira, Ana Filipa | Simões do Couto, Frederico | de Mendonça, Alexandre

Article Type: Research Article

Abstract: Cognitive decline in elderly people can be caused by a specific and treatable metabolic disorder, and the use of laboratory tests is recommended as part of the diagnostic workup of patients with dementia. Patients with mild cognitive impairment (MCI) are commonly investigated by a similar laboratory diagnostic workup, however it is not known whether this clinical practice is justified. In the present study, we compared the frequencies of laboratory abnormalities, and laboratory abnormalities relevant for cognitive impairment, in consecutive patients with MCI or dementia (all types) observed in a memory clinic setting. As much as 55.1% of patients …with MCI and 60.0% of patients with dementia had at least one abnormal laboratory value (a non-significant difference). The most frequent abnormal analysis was the serum cholesterol, that was high in 28.8% of patients with MCI and in 20.4% of patients with dementia. It was possible to detect, both in patients with MCI (1.5% and in patients with dementia (3.5%, a non-significant difference), abnormal metabolic values, indicating poorly controlled diabetes, renal failure, hyponatremia, folate or vitamin B12 deficiency and hyperthyroidism, which correction led to clinical improvement. The majority (62.5% of these alterations were previously unknown. These findings give support to the use of the laboratory diagnostic workup of dementia in patients with mild cognitive impairment. Show more

Keywords: Mild cognitive impairment, dementia, Alzheimer's disease, laboratory tests, blood analysis, urine analysis, metabolic cause

DOI: 10.3233/JAD-2006-10109

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 53-58, 2006

Authors: Mancuso, Michelangelo | Coppede, Fabio | Migliore, Lucia | Siciliano, Gabriele | Murri, Luigi

Article Type: Research Article

Abstract: Mitochondria play a critical role in several metabolic processes and apoptotic pathways, regulating life cycle from the cradle to the grave. Despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. Moreover, a growing body of evidence seems to indicate that oxidative stress, which is increased in damaged mitochondria, is an earlier event associated with neurodegeneration. Here we examine the current evidences in this field, which indicate a key role of mitochondria and oxidative stress in contributing to …the neurodegenerative processes. Show more

Keywords: Mitochondria, oxidative stress, ROS, mtDNA, neurodegeneration, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia

DOI: 10.3233/JAD-2006-10110

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 59-73, 2006

Authors: Larner, A.J. | Keynes, R.J.

Article Type: Research Article

Abstract: Aberrant neurite growth is one of the neuropathological signatures of the Alzheimer's disease brain, both around amyloid plaques and in the cortical neuropil. Disruption of neuroinhibitory or repulsive growth and guidance signals, as well as of neurotrophic or permissive signals, may contribute to this dystrophic growth. Hence, therapeutic efforts directed exclusively at restoring neurotrophic activity are unlikely to meet with success. The molecular species responsible for neuroinhibitory effects in the Alzheimer's disease brain are beginning to be elucidated.

Keywords: Alzheimer disease, growth factors, neuroinhibitors

DOI: 10.3233/JAD-2006-10111

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 75-80, 2006

Authors: Chohan, Muhammad Omar | Iqbal, Khalid

Article Type: Research Article

Abstract: Glutamate toxicity through NMDA receptor channels has long been central to the understanding of acute neuronal injury. Recent studies implicate similar events in chronic neurodegenerative diseases. Here, we analyze some of the most intriguing evidence for NMDA receptor-mediated cellular dysfunction and propose a mechanism by which hyperactive NMDA receptors might lead to neurofibrillary degeneration in Alzheimer's disease.

Keywords: Alzheimer's disease, tau, hyperphosphorylation, glutamate toxicity, NMDA receptors, memantine

DOI: 10.3233/JAD-2006-10112

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 81-87, 2006

Authors: de la Monte, Suzanne M. | Tong, Ming | Lester-Coll, Nataniel | Plater, Jr., Michael | Wands, Jack R.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is associated with major impairments in insulin and insulin-like growth factor (IGF) gene expression and signaling in the brain. These abnormalities increase with severity of dementia, and are associated with deficiencies in energy metabolism and acetylcholine homeostasis. The co-existence of brain insulin/IGF deficiency and resistance suggests that AD may represent a brain-specific form of diabetes, i.e. Type 3 diabetes. This hypothesis is supported by the findings in an experimental animal model in which intracerebral (ic) Streptozotocin (STZ) was used to deplete brain and not pancreatic insulin. The ic-STZ treatment produced brain-specific insulin depletion and insulin resistance are …associated with progressive neurodegeneration that shares many features in common with AD. We now demonstrate that early treatment with peroxisome-proliferator activated receptor agonists can effectively prevent ic-STZ-induced neurodegeneration and its associated deficits in learning and memory. These effects were mediated by increased binding to insulin receptors, reduced levels of oxidative stress and tau phosphorylation, and increased choline acetyltransferase expression in the brain, suggesting that insulin sensitizer agents may have therapeutic efficacy in early AD. Show more

Keywords: Type 3 diabetes, insulin, Alzheimer's disease, growth factor receptors, RT-PCR, Streptozotocin, peroxisome-proliferator activated receptor, insulin sensitizers, therapy

DOI: 10.3233/JAD-2006-10113

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 89-109, 2006

Authors: Thirumangalakudi, Lakshmi | Samany, Pezhman Ghatreh | Owoso, Akinkunle | Wiskar, Brandt | Grammas, Paula

Article Type: Research Article

Abstract: Data are emerging to support the idea that mediators of angiogenesis are found in the Alzheimer's disease (AD) brain. The objective of this study is to compare the expression of the angiogenic mediators vascular endothelial growth factor (VEGF), angiopoietin, and matrix metalloproteinases (MMPs) in the microcirculation of AD patients and age-matched controls. Our results indicate that angiopoietin-2 and VEGF are expressed by AD- but not control-derived microvessels. AD-derived microvessels also release higher levels of MMP-2 and MMP-9 compared to controls. The data show that despite high levels of MMP-9, assessed by western blot, MMP-9 activity is not detectable in AD …microvessels. In this regard we find high levels of the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in AD, but not control vessels. Furthermore, we explore the ability of thrombin, previously shown to be present in AD microvessels, to affect TIMP expression in cultured brain endothelial cells and find that thrombin causes up regulation of TIMP-1. These data show that angiogenic changes occur in the microcirculation of the AD brain and suggest that if these changes are contributory to disease pathogenesis, targeting the abnormal brain endothelial cell would provide a novel therapeutic approach for the treatment of this disease. Show more

Keywords: Alzheimer's disease, angiogenic proteins, microvessels, inflammation, thrombin

DOI: 10.3233/JAD-2006-10114

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 111-118, 2006

Article Type: Book Review

DOI: 10.3233/JAD-2006-10115

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 119-120, 2006

Article Type: Discussion

DOI: 10.3233/JAD-2006-10116

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 121-130, 2006

Article Type: Announcement

DOI: 10.3233/JAD-2006-10117

Citation: Journal of Alzheimer's Disease, vol. 10, no. 1, pp. 131-132, 2006