Journal of Alzheimer's Disease - Volume 10, issue 2-3

Authors: Connor, James R. | Lee, Sang Y.

Article Type: Research Article

Abstract: An imbalance in brain iron status has been established in Alzheimer's Disease (AD). This iron imbalance can impact plaque formation, amyloid processing, and expression of and response to inflammatory agents. In a more general sense, a deregulation of iron homeostasis underlies the generation of reactive oxygen species leading to oxidative damage. Thus, loss of iron homeostasis can be central to the pathogenic events in AD. Recently a number of studies have begun to investigate the frequency of mutations in the HFE gene in AD. Mutations in the HFE gene occur more frequently in Caucasians than any other mutation. The two …most common mutations of HFE are the C282Y (2% of the total population) and the H63D (9%. Mutations in this gene are associated with loss of iron homeostasis, alterations in inflammatory responses and in its most severe form, a clinical disorder known as Hemochromatosis. The C282Y mutation is more frequently associated with Hemochromatosis and the frequency of the H63D mutation is receiving increasing attention in neurodegenerative disorders. This review summarizes the data on HFE mutations in neurodegenerative disorders and what is known about HFE in the brain and the cell biology underlying the HFE mutation. Show more

DOI: 10.3233/JAD-2006-102-311

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 267-276, 2006

Authors: Dewji, Nazneen N.

Article Type: Research Article

Abstract: Molecular genetic studies of familial Alzheimer's disease by 1995 had clearly implicated three proteins as critical to Alzheimer's disease (AD), the amyloid-β protein precursor (AβPP) and the two homologous presenilins, PS-1 and PS-2. To account for the roles of these proteins in AD, we had proposed that as an early and critical step in the mechanisms that lead to AD, the PS on the surface of a brain cell engages in a specific receptor-ligand intercellular interaction with AβPP on the surface of a neighboring cell. This cell-cell interaction is required to trigger off a cascade of processes that lead to …the production of amyloid-β (Aβ) from AβPP, leading to AD. At about this time, however, many established AD researchers had obtained data that appeared to disagree with our proposed mechanism. Their immediate objections to our proposal were based on their conclusions that 1) The PS proteins were exclusively intracellular, and were not expressed at the cell surface, and 2) The topography of the PS proteins in intracellular membranes exhibits either 6 or 8-TM spanning domains, not 7. Here we discuss the evidence for the 6-TM, 7-TM, 8-TM and other models of PS topography and offer possibilities for the differences in interpretation of the various sets of data. We review the experimental demonstration of the cell-surface expression and the 7-TM structure of PS, the functional consequences of this structure, and the findings that PS-1 and PS-2 are members of the superfamily of 7-TM heterotrimeric G-protein coupled receptors (GPCRs). Show more

DOI: 10.3233/JAD-2006-102-312

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 277-290, 2006

Authors: Dolev, Iftach | Michaelson, Daniel M.

Article Type: Research Article

Abstract: The amyloid-β (Aβ) peptide is a major constituent of the brain senile plaques that characterize Alzheimer's disease (AD). Converging observations led to the formulation of the amyloid hypothesis whereby the accumulation of soluble aggregates and insoluble Aβ deposits is the primary event in AD pathogenesis. Furthermore, the apoE4 isoform of apolipoprotein E, a major prevalent genetic risk factor of AD, is associated with increased Aβ deposition. To investigate the initial stages of the amyloid cascade in vivo and how this is affected by apoE4, we studied the effects of prolonged inhibition and subsequent reactivation of the Aβ-degrading enzyme, …neprilysin, on aggregation and deposition of Aβ in apoE transgenic and control mice. The results revealed that Aβ deposition in vivo is initiated by aggregation of Aβ42, which is followed by reversible deposition of both Aβ42 and Aβ40, along with growth of the deposits, and by their subsequent irreversible fibrillization. The initiation of Aβ42 deposition is accelerated isoform-specifically by apoE4, whereas the growth and dissolution of the Aβ deposits as well as their fibrillization are similarly stimulated by the various apoE isoforms. Interestingly, Aβ deposition was associated with increased gliosis, which may reflect early pathological interactions of β with the brain's parenchyma. Show more

Keywords: Amyloid β, Apolipoprotein E4, neprilysin, transgenic, aggregation

DOI: 10.3233/JAD-2006-102-313

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 291-301, 2006

Authors: Solfrizzi, Vincenzo | Colacicco, Anna Maria | D'Introno, Alessia | Capurso, Cristiano | Parigi, Angelo Del | Capurso, Sabrina A. | Torres, Francesco | Capurso, Antonio | Panza, Francesco

Article Type: Research Article

Abstract: A possible role of the macronutrients and the basic elements of carbohydrates (glucose administration or depletion), proteins (amino acids such as tryptophan and tyrosine), and fat (unsaturated fatty acids) was recently proposed for age-related changes of cognitive function, and the cognitive decline of degenerative (AD) or vascular origin. The availability and utilization of glucose has been implicated in cognitive function not only as a result of nutritional and systemic metabolic conditions, but also, although speculatively, as a crucial phase of the mechanism of action of molecules used as cognitive-enhancers. Furthermore, many lines of evidence have focused on the importance of …oxidative stress mechanisms and free radical damage in AD pathogenesis. In addition, epidemiological studies have recently reported an association between alcohol and the incidence of AD and predementia syndromes. Foods with large amounts of aluminium-containing additives or aluminium from drinking water may affect the risk of developing AD, aluminium more likely acting as a cofactor somewhere in the cascade of events leading to the demented brain. A role for other metals in dementia have been speculated, given the encouraging results reported from studies on peripheral zinc concentrations, zinc supplementation, serum copper, either bound with ceruloplasmin or not, and iron metabolism in AD. Nonetheless, more data are needed to support a possible role of these metals in dementing diseases. Healthy diets, antioxidant supplements, and the prevention of nutritional deficiencies or exposure to foods and water with high content of metals could be considered the first line of defence against the development and progression of cognitive decline. Show more

Keywords: Carbohydrates, proteins, diet, aluminium, copper, iron, dementia, Alzheimer's disease, vascular dementia

DOI: 10.3233/JAD-2006-102-314

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 303-330, 2006

Authors: Domingo, Jose L.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain. Although the causes of AD remain still unknown, it seems that certain environmental factors may be involved in the etiology and pathogenesis of the disease. While AD is associated with the abnormal aggregation of β-amyloid protein in the brain, evidence shows that certain metals play a role in the precipitation and cytotoxicity of this protein. Among these metals, the potential role of aluminum as a possible ethiopathogenic factor in AD has been especially controversial. This review is mainly focused on the role of …aluminum and metals such as copper and zinc in AD, as well as on metal chelator therapy as a potential treatment for AD. The effects of desferrioxamine and other Al chelating agents have been reviewed. The role of the metal chelator clioquinol in AD, which has been reported to reduce β-amyloid plaques, presumably by chelation associated with copper and zinc, is also revised. Finally, the potential role of silicon in AD is also discussed. Show more

Keywords: Alzheimer's disease, aluminum, chelating agents, clioquinol, silicon

DOI: 10.3233/JAD-2006-102-315

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 331-341, 2006

Article Type: Discussion

DOI: 10.3233/JAD-2006-102-316

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 343-349, 2006

Article Type: Announcement

DOI: 10.3233/JAD-2006-102-317

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 351-352, 2006