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

Authors: Shea, Thomas B. | Lyons-Weiler, James | Rogers, Eugene

Article Type: Research Article

Abstract: Increased levels of homocysteine (HC), arising in some situations via deficiencies in folate – an essential cofactor in metabolic regulation of HC – have long been known to contribute to cardiovascular disorders and stroke. More recently, clinical studies implicate increased HC and reduced folate with neurodegenerative conditions including Alzheimer's disease. It has remained unclear from clinical studies whether the neurotoxicity of increased HC and/or reduced folate is derived from direct detrimental effects on neurons themselves, or is instead derived indirectly following perturbation of nervous system vasculature. However, recent reports from several laboratories provide evidence that HC not only induces direct …neurotoxicity, but also potentiates both amyloid-beta and glutamate neurotoxicity. These latter studies leave open the possibility that even mild elevations in HC may place neurons at risk for additional trauma. The potential contribution of folate deficiency and resultant increases in HC to neurodegeneration in AD, and therapeutic approaches to alleviate their impact, is discussed. Show more

DOI: 10.3233/JAD-2002-4401

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 261-267, 2002

Authors: Grant, Philip | Pant, Harish C.

Article Type: Research Article

Abstract: At autopsy, a most distinctive pathology seen in Alzheimer's disease (AD) brains is numerous abnormal neurons filled with neurofibrillary tangles (NFTs) containing stable complexes of hyperphosphorylated tau (PHF), neurofilaments and various kinases, among other proteins. Though these neuronal aggregates have been actively studied, their nature and origin are still poorly understood. Our studies of regulation of phosphorylation in neurons of the squid giant fiber system, using P13suc1 affinity chromatography, suggest that neuronal phosphorylation of cytoskeletal proteins is compartmentalized into active axonal and inactive cell body-specific multimeric complexes of kinases, substrates and phosphatases. To determine whether such compartment-specific phosphorylation complexes …are present in human brains, we separated gray matter (enriched in cell bodies) and white matter (enriched in axons) from normal and AD brains and studied the total kinase activities in lysates, pellets and P13suc1 complexes. In addition, Western blot analysis was used to characterize the proteins associated with P13suc1 multimeric complexes extracted from gray and white matter. We tested the hypothesis that P13 phosphorylation complexes were abnormally compartmentalized in AD neurons with the more active complexes shifted to cell bodies (gray matter) instead of axons (white matter). We found that (1) endogenous and exogenous substrate-dependent kinase activities of AD and control brain extracts were similar in both gray and white matter. (2) Long post mortem times tend to erase any differences in kinase activity between control and AD extracts. In contrast to shorter post mortem times (4.5–10 hrs), long post mortem times (13–34 hrs) significantly minimize the variances in kinase activities between control and AD brain extracts suggesting that cell death and proteolysis may eliminate any intrinsic differences in enzyme activities. (3) Except for the significantly higher level of histone phosphorylation in control white extracts, the kinase activities of P13suc1 -derived multimeric complexes from gray and white matter were also similar in control and AD brains. Here, too, variances between control and AD distributions were significantly different (p < 0.001–0.02) suggesting that the P13 complexes were different. We also found differences in the Western blot profiles of P13suc1-associated kinases and cytoskeletal proteins; higher expression of phosphorylated NF-H and PHF-tau in gray matter of AD brains was detected. We believe that such differences in P13 complexes from human control and AD brain samples displaying extensive heterogeneity in age, post mortem time and clinical history, may be important. Show more

DOI: 10.3233/JAD-2002-4402

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 269-281, 2002

Authors: Brunelle, Patrick | Rauk, Arvi

Article Type: Research Article

Abstract: The Radical Model of Alzheimer's Disease (AD) is presented in some detail. The model provides a unified picture for the role of the amyloid beta peptide (Aβ), Met35, copper ions, oxygen, beta sheet secondary structure, and the generation of hydrogen peroxide, in mediating oxidative stress in AD. It predicts a role for glycyl radicals as long-lived species which can transport the damage into cell membranes and initiate lipid peroxidation. Previous work has established the thermodynamic and kinetic viability of most of the steps. In the present work, QM/MM and Amber calculations reveal that self assembly of antiparallel β-sheet which brings …Met35 into the required close proximity to a glycine residue is more likely if the residue is Gly29 or Gly33, than any of the other four glycine residues of Aβ. Show more

DOI: 10.3233/JAD-2002-4403

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 283-289, 2002

Authors: Bhat, Ratan V. | Leonov, Sergey | Luthman, Johan | Scott, Clay W. | Lee, Chi-Ming

Article Type: Research Article

Abstract: Withdrawal of NGF (NGF-W) in PC12 cells leads to caspase and GSK3βactivation which results in cell death. Our recent findings suggest that inhibition of GSK3β promotes PC12 cell survival after NGF-W. To determine whether these pathways interact from a signalling perspective, we compared the effects of BAF (a general caspase inhibitor), Li+ (a GSK3βinhibitor) and insulin on NGF-W induced PC12 cell death. Maximal increase in DNA fragmentation was observed 3 h after NGF-W and was inhibited by BAF (7.5 μM), Li+ (IC50 = 2 mM) and insulin (IC50 = 100 nM). BAF inhibited caspase-3 activity and …delayed cell death up to 6~h after NGF-W indicating that caspase inhibition is sufficient to prevent apoptosis. BAF had no major effect on GSK3βactive site phosphorylation or activity suggesting the caspase pathway does not regulate GSK3β activity. Conversely, Li+ inhibited caspase activity by only 20% after NGF-W. Overexpression of dominant negative mutants of GSK3β also inhibited apoptosis, but had only a minor effect on caspase activity after NGF-W. Taken together, these results suggest that GSK3β is upstream of caspase signalling, and exerts a small effect on the caspase pathway. Show more

DOI: 10.3233/JAD-2002-4404

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 291-301, 2002

Authors: Nandoe, Rishi D.S. | Scheltens, Philip | Eikelenboom, Piet

Article Type: Research Article

Abstract: The authors describe a case of a 55 year old woman who was diagnosed with Alzheimer's disease 1.5 years after a car accident in which she experienced a mild concussion. Extensive history taking disclosed no cognitive changes prior to the car accident. The case is discussed in view of the inflammation hypothesis regarding Alzheimer's disease and the role of the apolipoprotein E4 genotype of the patient.

Keywords: Alzheimer's disease, head trauma, inflammation, atrophy, cholinesterase inhibitors, ApoE, amyloid

DOI: 10.3233/JAD-2002-4405

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 303-308, 2002

Authors: Li, Qiao-Xin | Campbell, Bruce C.V. | McLean, Catriona A. | Thyagarajan, Domimic | Gai, Wei-Ping | Kapsa, Robert M. | Beyreuther, Konrad | Masters, Colin L. | Culvenor, Janetta G.

Article Type: Research Article

Abstract: α-Synuclein (αSN) has been implicated in Parkinson's Disease (PD) and αSN is a major component of Lewy bodies (LBs). This study explored platelets as a model system for study of αSN metabolism and platelet αSN as a diagnostic marker for PD. We used Western blot analysis to characterize and compare platelet and brain α-, β- and γSN; and to quantitate αSN levels in platelets from PD and age-matched controls. We found that platelets contain full-length αSN and 6 and 12 kDa fragments, and γSN-like protein. αSN and γSN were not secreted by thrombin-activated platelets. Furthermore, we also found that the …αSN and γSN levels in sporadic PD patients and age-matched normal controls were not significantly different. This indicates that platelet αSN or γSN is not a suitable peripheral diagnostic marker for PD. Platelets may be used for study of αSN and γSN metabolism, and may give some broad insight into the normal functions of αSN and γSN. Show more

Keywords: Parkinson's disease, α-synuclein, γ-synuclein, platelet

DOI: 10.3233/JAD-2002-4406

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 309-315, 2002

Authors: Sabbagh, Marwan N. | Lukas, Ronald J. | Sparks, D. Larry | Reid, Richard T.

Article Type: Research Article

Abstract: Cholinergic dysfunction is one of the cornerstones of Alzheimer's disease (AD) pathology. Reviewed here is evidence evaluating relationships between smoking, nicotine exposure, nicotinic cholinergic signaling, and AD. Epidemiological studies initially indicating a lower incidence of AD in smokers now suggest conflicting results. Clinicopathological findings also are mixed as to how smoking behavior affects manifestation of AD markers. Studies that show nicotine-induced increases in nicotinic acetylcholine receptors (nAChR) and protection against age-related nAChR decline contrast, perhaps in a functionally relevant way, to losses of nAChR in AD. Although epidemiological, clinicopathological, and functional studies in humans do not present a cohesive picture, …much {\it in vitro} data suggests neuroprotective properties of nicotine when used in models of neurodegenerative disorders. Studies of nicotine and nicotinic agonist effects on cognitive function in the non-demented and in AD are not compelling. More work is needed to ascertain whether acute or repetitive activation of nAChR with acute or intermittent exposure to nicotine or the persistent inactivation of nAChR with chronic nicotine exposure is a therapeutic objective and/or explains any pro-cognitive effects of those drugs. Other studies show complex interactions between nAChR, nicotinic agonists, and agents implicated in AD etiology. Thus, while controversies still exist, ongoing research is illuminating how nicotinic receptor changes and functions may be relevant to clinical, pathological and neurochemical changes that occur in AD. Show more

DOI: 10.3233/JAD-2002-4407

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 317-325, 2002

Authors: Jellinger, Kurt A. | Seppi, Klaus | Wenning, Gregor K.

Article Type: Letter

DOI: 10.3233/JAD-2002-4408

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 327-328, 2002

Authors: Rafael, Hernando | Fernández, Eudocio | Ayulo, Víctor

Article Type: Letter

DOI: 10.3233/JAD-2002-4409

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 329-330, 2002

Authors: Qiu, Chengxuan | Fratiglioni, Laura

Article Type: Other

DOI: 10.3233/JAD-2002-4410

Citation: Journal of Alzheimer's Disease, vol. 4, no. 4, pp. 331-331, 2002