Journal of Alzheimer's Disease - Volume 6, issue 3

Authors: LeVine, III, Harry

Article Type: Research Article

Abstract: The second generation of therapeutic strategies for Alzheimer's disease (AD) embraces the Amyloid Hypothesis, which asserts that through a series of events not completely understood, misfolding of the amyloid-β (Aβ) peptide is a primary event eliciting neurodegeneration and AD pathology. A variety of approaches are being tried to interrupt the disease process, including reducing the production of the Aβ peptide, inhibiting its aggregation, and promoting its removal, for example via immunotherapy. The success of anti-Aβ disease-modifying approaches in eliminating the postulated etiologic form(s) of the peptide will ultimately depend on biological clearance and degradation of the various forms of the …Aβ peptide from the brain compartment. Little is known about exchange of theβ peptide between the brain and blood. Increased understanding of this process in experimental animal models and humans, and how it changes with aging, will likely open new therapeutic avenues. It will also be needed to properly design early clinical trials to verify the efficacy of potential drug candidates working through the Aβ peptide. Show more

Keywords: oligomer, proteolysis, aging, misfolded proteins, deposition, peripheral sink

DOI: 10.3233/JAD-2004-6311

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 303-314, 2004

Authors: Miu, Andrei C. | Olteanu, Adrian I. | Miclea, Mircea

Article Type: Research Article

Abstract: The persistence of neuroscientists in exploring aluminium's (Al) possible contribution to the pathogenesis of Alzheimer's disease (AD) has resulted in a wealth of researches detailing the biological toxicity of this metal. However, to date, there have been few accounts of the interference of Al with aging and its relevance to the pathogenesis of AD. We investigated the behavioral and the ultrastructural signatures of Al in the hippocampus on young and aging rats which were exposed for three months to aluminium gluconate. The aging animals displayed decreased scores of activity and emotionality, and the Al-exposed aging males had altered emotional reactivity …behaviors. The electron-microscopic analysis indicated that Al promoted in the aging hippocampus a variety of cellular and ultrastructural degenerative signs, such as granulo-vacuolar degenerations, deposition of lipofuscin and amyloid in the cytoplasm of neurons and astrocytes, and in extracellular compartments, Hirano bodies, demyelination and the atrophy of the mitochondria. Moreover, the quantitation of myelin sheath width and the diameter of mitochondria measured on randomly selected samples confirmed that myelin and mitochondria are primary targets of Al's toxicity. Demyelination and mitochondrial atrophy seemed more advanced in the hippocampus of Al-exposed aging males, supporting the effect of sex suggested by the behavioral results. These findings and other collateral results also reported here are discussed in the context of a possible involvement of Al in AD, mediated by aging and catalyzed by hepatic morphopathology. Show more

Keywords: aluminum, aging, mitochondria, myelin, Alzheimer's disease

DOI: 10.3233/JAD-2004-6312

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 315-328, 2004

Authors: Flicker, L. | Martins, R.N. | Thomas, J. | Acres, J. | Taddei, K. | Norman, P. | Jamrozik, K. | Almeida, O.P.

Article Type: Research Article

Abstract: The ε4 allele of apolipoprotein E (APOE), and the plasma levels of APOE, amyloid β-protein precursor, amyloid β1-40 (Aβ40) and homocysteine (Hcy) have all been correlated with the presence of dementia. Mutations in the methylnetetrahydrofolate reductase enzyme (MTHFR) have been associated with elevated levels of Hcy. This study explored the association of these factors with cognition and depression in community dwelling older men. Two hundred and ninety-nine men, mean age 78.9 years (SD 2.8), were studied in this cross-sectional survey. Mean plasma Hcy was 13.5 (SD 5.3) μmol/L. The MTHFR genotype had no obvious impact on Hcy levels. Ln …Hcy and Ln Aβ40 were both inversely correlated with calculated glomerular filtration rate (cGFR), r = -0.41 (p < 0.001) and r = -0.28 (p < 0.001), respectively. There was a positive correlation between Ln Hcy and Ln Aβ40, r = 0.19 (p < 0.001), which remained significant after adjusting for cGFR, with a doubling of Hcy associated with a 24% increase of Aβ40. The e4 allele was associated with increased depressive symptoms as measured by the Geriatric Depression Scale-15, Odds ratio (OR) = 2.59 (95%CI 1.06–6.34) and poorer performance on the Clock Drawing Test, OR = 2.32 (95% CI: 1.25–4.29). There was a positive association between Aβ40 and Hcy, even after adjustment for cGFR in this sample of well, community dwelling older men. This association may help elucidate the link between elevated levels of Hcy and Alzheimer's disease. Show more

Keywords: dementia, amyloid protein, Apolipoprotein E, cognition, depression, homocysteine, methylnetetrahydrofolate reductase, geriatric

DOI: 10.3233/JAD-2004-6313

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 329-336, 2004

Article Type: Discussion

DOI: 10.3233/JAD-2004-6314

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 337-342, 2004

Article Type: Other

DOI: 10.3233/JAD-2004-6315

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 343-343, 2004

Article Type: Obituary

DOI: 10.3233/JAD-2004-6316

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 345-345, 2004

Article Type: Announcement

DOI: 10.3233/JAD-2004-6317

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 347-352, 2004