Journal of Alzheimer's Disease - Volume 11, issue 4

Authors: Mizoroki, Tatsuya | Meshitsuka, Shunsuke | Maeda, Sumihiro | Murayama, Miyuki | Sahara, Naruhiko | Takashima, Akihiko

Article Type: Research Article

Abstract: Etiological studies suggest that aluminum (Al) intake might increase an individual's risk of developing Alzheimer's disease (AD). Biochemical analysis data on the effects of Al, however, are inconsistent. Hence, the pathological involvement of Al in AD remains unclear. If Al is involved in AD, then it is reasonable to hypothesize that Al might be involved in the formation of either amyloid plaques or neurofibrillary tangles (NFTs). Here, we investigated whether Al might be involved in NFT formation by using an in vitro tau aggregation paradigm, a tau-overexpressing neuronal cell line (N2a), and a tau-overexpressing mouse model. Although Al induced tau …aggregation in a heparin-induced tau assembly assay, these aggregates were neither thioflavin T positive nor did they resemble tau fibrils seen in human AD brains. With cell lysates from stable cell lines overexpressing tau, the accumulation of SDS-insoluble tau increased when the lysates were treated with at least 100 μM Al-maltolate. Yet Al-maltolate caused illness or death in transgenic mice overexpressing human tau and in non-transgenic littermates well before the Al concentration in the brain reached 100 μM. These results indicate that Al has no direct link to AD pathology. Show more

Keywords: Alzheimer's disease, aluminum, tau aggregation, tau fibril formation, tau transgenic mouse

DOI: 10.3233/JAD-2007-11401

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 419-427, 2007

Authors: Savory, John | Ghribi, Othman

Article Type: Article Commentary

DOI: 10.3233/JAD-2007-11402

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 429-430, 2007

Authors: Takashima, Akihiko

Article Type: Article Commentary

DOI: 10.3233/JAD-2007-11403

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 431-432, 2007

Authors: Joseph, J.A. | Carey, A. | Brewer, G.J. | Lau, F.C. | Fisher, D.R.

Article Type: Research Article

Abstract: We have shown previously that dietary blueberry (BB) extract supplementation (S) reversed several parameters of neuronal and behavioral (e.g., cognition) aging in rodents. Additionally, findings indicate that COS-7 cells transfected with muscarinic receptor subtypes (e.g., M1) showed decrements in Ca2+ clearance following depolarization (Ca2+ Recovery time, Ca2+ RT) that were antagonized by BB. Since it has been postulated that at least part of the loss of cognitive function in aging may be dependent upon a dysregulation in calcium homeostasis (i.e., Ca2+ RT), we assessed whether: a) Ca2+ RT would be altered in dopamine (DA)- or amyloid beta (Aβ)-exposed …cultured primary hippocampal neuronal cells (HNC), and b) BB pre-treatment of the cells would prevent these deficits. Thus, control or BB (0.5 mg/ml)-treated HNC were exposed to DA (0.1 mM, 2 hrs), Aβ(40) (25 μM, 24 hrs), Aβ(42) (25 μM, 24 hrs), and Aβ(25–35) (25 μM, 24 hrs), and Ca2+ RT following KCl-induced depolarization assessed. Ca2+ RT was assessed as the % of HNC showing recovery to 50%–70% of control at 5, 10, or 15 min after depolarization. Results indicated that DA significantly lowered Ca2+ RT in the HNC at all time points examined after depolarization. However, BB treatment selectively prevented these declines in Ca2+ RT. In the case of Aβ, the greatest effects on Ca2+ RT were seen when the hippocampal cells were Aβ(42)-treated. These effects were antagonized by BB treatment. Aβ(40) produced fewer deficits on Ca2+ RT than those seen when the HNC were pre-treated with either A2+ (42) or A2+ (25–35), but BB was relatively ineffective in antagonizing the deficits in Ca2+ RT produced by A2+ (40) or A2+ (25–35). Additional analyses indicated that BBs may be exerting their protective effects in the hippocampal cells by altering levels of phosphorylated MAPK, PKCγ, and phosphorylated CREB. Therefore it appears that at least part of the protective effect of BBs may involve alterations in stress signaling. Show more

DOI: 10.3233/JAD-2007-11404

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 433-446, 2007

Authors: Tripathy, Debjani | Thirumangalakudi, Lakshmi | Grammas, Paula

Article Type: Research Article

Abstract: Inflammatory mediators are highly expressed in the Alzheimer's disease (AD) brain. We have shown that in AD the cerebral microcirculation is a rich source of cytokines and chemokines including interleukins (IL) 1β, IL-6, IL-8, tumor necrosis factor-α, and monocyte chemoattractant protein-1. However, the factors that regulate expression of these inflammatory proteins have not been defined. The objective of this study is to compare expression of macrophage inflammatory protein 1-α (MIP-1α) in brain microvessels isolated from AD patients to vessels from age-matched controls and further to determine whether expression of MIP-1α in brain endothelial cells is altered by oxidative stress. The …data show that brain AD-derived microvessels express high levels of MIP-1α mRNA and release high levels of MIP-1α protein compared to brain microvessels isolated from controls. Treatment of brain endothelial cell cultures with menadione, a superoxide releasing compound, hydrogen peroxide, lipopolysacharride, or oxidatively modified low density lipoproteins (LDL) (Ox-LDL, HNE-LDL) results in a dose- dependent increase in MIP-1α mRNA levels and MIP-1α release into the media. These results suggest that oxidative and lipid insults to the brain microvasculature are likely to contribute to the inflammatory milieu of the AD brain. Show more

Keywords: Microvessels, inflammation, oxidative stress, chemokines, MIP-1α, vascular

DOI: 10.3233/JAD-2007-11405

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 447-455, 2007

Authors: Fiala, Milan | Cribbs, David H. | Rosenthal, Mark | Bernard, George

Article Type: Research Article

Abstract: Innate immunity provides the first line of defense by recognizing pathogen-associated microbial patterns and inducing key co-stimulatory molecules and cytokines, which activate the mechanisms of the adaptive immune response. Innate immune cells perform phagocytosis, which can clear pathogens and tissue waste products but may also contribute to tissue injury due to harmful side effects of inflammation. Genetic studies of APOE4, cytokine polymorphisms and overexpression of inflammatory genes suggest that chronic inflammation may have adverse effects in patients with sporadic Alzheimer's disease. However, a vaccine against amyloid-β induced beneficial clearance of amyloid-β deposits, possibly through Fc receptor-mediated stimulation of microglial and …macrophage uptake. A reconciliation of these two pathogenetic mechanisms is crucial to future progress in immune diagnosis and effective therapy. This may be possible by extending our recent observations suggesting that phagocytosis of amyloid-β by macrophages is excellent in normal subjects but is deficient in most AD patients. Thus increased proinflammatory cytokine levels and activated microglia and macrophages in patients may be compensatory for defective clearance of amyloid-β. Consequently, therapeutic interventions that increase phagocytosis of amyloid-β might decrease brain inflammation as well as reduce inflammation-induced neurodegeneration. Finally, peripheral blood leukocytes are a superior model system for investigation of innate immune dysfunction in Alzheimer's disease. Show more

Keywords: Amyloid-β, inflammation, innate immunity

DOI: 10.3233/JAD-2007-11406

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 457-463, 2007

Authors: Quintana, Carmen

Article Type: Article Commentary

DOI: 10.3233/JAD-2007-11407

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 465-467, 2007

Authors: Dobson, Jon | Collingwood, Joanna F.

Article Type: Article Commentary

DOI: 10.3233/JAD-2007-11408

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 469-470, 2007

Authors: Bakchine, S. | Loft, H.

Article Type: Research Article

Abstract: Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist currently approved for the treatment of moderate to severe Alzheimer's disease (AD). A 24-week, double-blind, placebo-controlled, study (Study 99679) conducted in Europe evaluated the efficacy and tolerability of 20mg/day memantine in patients with mild to moderate AD. Patients were randomised to either memantine or placebo in a 2:1 ratio. Efficacy was primarily assessed as change from baseline in ADAS-cog and CIBIC-plus score. Of 470 patients randomised and treated (memantine, n=318; placebo, n=152), 85% and 91% completed the study. Memantine-treated patients showed statistically significant improvement relative to placebo at weeks 12 and …18, and numerical superiority at week 24 on both efficacy scales. The lack of significance at week 24 was attributed to an unexpectedly high placebo response. Memantine was well tolerated with an adverse event profile similar to placebo. The data presented support the efficacy of memantine in mild to moderate AD. Show more

Keywords: Memantine, Alzheimer's disease, mild to moderate, NMDA receptor

DOI: 10.3233/JAD-2007-11409

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 471-479, 2007

Authors: Rice, Stephen G. | Nowak, Lee | Duysen, Ellen G. | Lockridge, Oksana | Lahiri, Debomoy K. | Reyes, Patricio F.

Article Type: Research Article

Abstract: The ‘cholinergic hypothesis’, based on the correlation of the reduction of cholinergic activity in Alzheimer's disease (AD) with cognition and memory, is currently the most widely-held view for AD. Drug treatments for AD focus mainly on inhibition of acetylcholinesterase (AChE), and to some extent butyrylcholinesterase (BChE). In addition to changes in AChE in AD, there is a rise in the level of the sister enzyme BChE. However, the role of the two cholinesterases is poorly understood in vivo. We characterized several proteins immunohistochemically in brain sections from AChE nullizygote (AChE−/−) and wild type AChE+/+ mice. Previous studies had shown that …AChE−/− mouse tissues are devoid of AChE activity and that the overall cholinesterase activity is significantly decreased in the knockout group [16]. Despite the differences of cholinesterase activity, we found no significant structural alterations between the experimental groups. Immunohistochemical examination revealed no neuronal, dendritic, astrocytic, synaptic, microglial, and endothelial differences between AChE−/− and AChE+/+ mice. Similarly, the histochemical examination showed no morphologic alterations between AChE−/− and AChE+/+ mice. Our studies show that neither the absence of AChE nor the presence exclusively of BChE is associated with neuroglial and vascular pathology. Show more

Keywords: Alzheimer's disease, cholinergic hypothesis, acetylcholinesterase, butyrylcholinesterase, neuron specific enolase, glial fibrillary acidic protein, synaptophysin, CD34, HLA-DP

DOI: 10.3233/JAD-2007-11410

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 481-489, 2007

Authors: Coyle, Joseph T. | Geerts, Hugo | Sorra, Karin | Amatniek, Joan

Article Type: Research Article

Abstract: Galantamine is an approved treatment for mild to moderate Alzheimer's disease, with demonstrated benefits for cognition and functional ability in human studies. The mechanism of action that is most generally recognized as underlying the clinical benefits of galantamine is inhibition of brain acetylcholinesterase (AChE). However, an increasing body of evidence suggests that an additional mechanism, most likely allosteric modulation of nicotinic acetylcholine receptors (nAChRs), may contribute to the therapeutic effects of galantamine. This review summarizes the research on this additional mechanism, with emphasis on data derived from in vivo animal studies and open-label hypothesis-generating studies in humans. In general, these …studies provide evidence of effects beyond those of AChE inhibition alone, most notably in comparisons with other AChE inhibitors, in which galantamine produced similar or greater effects at doses that provided lower levels of brain AChE inhibition. The use of nAChR agonists and antagonists in some of these studies lends support to the proposed allosteric potentiating ligand activity of galantamine at nAChRs. This dual action of galantamine may account for its therapeutic profile. Show more

Keywords: Galantamine, donepezil, nicotinic acetylcholine receptors, Alzheimer's disease, allosteric potentiation, acetylcholinesterase inhibition

DOI: 10.3233/JAD-2007-11411

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 491-507, 2007

Authors: Emre, Murat | Cummings, Jeffrey L. | Lane, Roger M.

Article Type: Research Article

Abstract: Parkinson's disease dementia (PDD) and Alzheimer's disease (AD) are both characterized by cognitive abnormalities, neuropsychiatric symptoms, and cholinergic deficits. We reviewed data from large, placebo-controlled clinical trials conducted with rivastigmine in patients with PDD and AD to evaluate similarities and differences in response to treatment. In placebo groups, AD patients appeared to show more rapid cognitive decline than those with PDD. Treatment effects (rivastigmine versus placebo) on cognitive performance over 6 months were quantitatively similar in both populations, but qualitatively different: in AD, cognitive abilities were stabilized by rivastigmine compared to declines in placebo groups, whereas in PDD symptomatic improvements …above baseline drove treatment effects while placebo patients had limited change. On activities of daily living, stabilization (rather than improvement) was observed in both dementia types. A more aggressive course of placebo decline, and greater treatment differences (rivastigmine versus placebo), were seen in sub-populations of both PDD and AD patients with hallucinations at baseline. The safety and adverse event profiles were comparable in the two populations. In conclusion, the magnitude of effect with rivastigmine versus placebo is quantitatively comparable in patients with AD and PD, but the treatment effect tended to be one of stabilization in AD, while in PDD improvements over baseline were seen. In both populations, hallucinations may identify patients who are likely to be more treatment-responsive. Show more

Keywords: Alzheimer's disease, cholinesterase inhibitors, parkinson's disease dementia, rivastigmine

DOI: 10.3233/JAD-2007-11412

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 509-519, 2007

Article Type: Announcement

DOI: 10.3233/JAD-2007-11413

Citation: Journal of Alzheimer's Disease, vol. 11, no. 4, pp. 521-523, 2007