Journal of Alzheimer's Disease - Volume 19, issue 4

Authors: Smith, Danielle G. | Ciccotosto, Giuseppe D. | Tew, Deborah J. | Perez, Keyla | Curtain, Cyril C. | Boas, John F. | Masters, Colin L. | Cappai, Roberto | Barnham, Kevin J.

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ) toxicity is thought to be responsible for the neurodegeneration associated with Alzheimer's disease. While the mechanism(s) that modulate this toxicity are still widely debated, it has previously been demonstrated that modifications to the three histidine residues (6, 13, and 14) of Aβ are able to modulate the toxicity. Therefore to further elucidate the potential role of the histidine (H) residues in Aβ toxicity, we synthesized Aβ peptides with single alanine substitutions for each of the three histidine residues and ascertained how these substitutions affect peptide aggregation, metal binding, redox chemistry, and cell membrane interactions, factors which have …previously been shown to modulate Aβ toxicity. Aβ42 H13A and Aβ42 H6A modified peptides were able to induce significant cell toxicity in primary cortical cell cultures at levels similar to the wild-type peptide. However, Aβ42 H14A did not induce any measurable toxicity in the same cultures. This lack of toxicity correlated with the inability of the Aβ42 H14A to bind to cell membranes. The interaction of Aβ with cell membranes has previously been shown to be dependent on electrostatic interactions between Aβ and the negatively charged head group of phosphatidylserine. Our data suggests that it is the imidazole sidechain of histidine 14 that modulates this interaction and strategies inhibiting this interaction may have therapeutic potential for Alzheimer's disease. Show more

Keywords: Amyloid, cell membrane, neurotoxicity, phosphatidylserine

DOI: 10.3233/JAD-2010-1334

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1387-1400, 2010

Authors: Koedam, Esther L.G.E. | Lauffer, Vivian | van der Vlies, Annelies E. | van der Flier, Wiesje M. | Scheltens, Philip | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common cause of dementia at older age. Although less prevalent before the age of 65 years, it is still the most frequent cause of early-onset dementia followed by frontotemporal dementia. The typical presentation of AD is memory dysfunction, however, presentations with prominent cognitive impairment in other domains besides memory, like prominent apraxia, language problems, or executive dysfunction, may occur and are relatively more common in early-onset AD. In this retrospective descriptive study, we determined the prevalence of non-memory presentations in a large sample of early-onset AD patients compared to late-onset AD. The clinical files …of 270 patients with AD starting before the age of 65 years and 90 patients with late-onset AD (⩾ 65 years) were reviewed to assess clinical characteristics. Patients were classified as memory presentation and non-memory presentation according to their clinical presentation. The mean age of the early-onset group was 56 ± 5 years and 74 ± 6 years for the late-onset group. A third of the early-onset AD group presented with non-memory symptoms compared to only 6% in the late-onset group (p < 0.001). Within the group with non-memory presentations, apraxia/visuospatial dysfunction was the most prevalent presenting symptom (12%). Patients with early-onset AD often present with a non-memory phenotype, of which apraxia/visuospatial dysfunction is the most common presenting symptom. Atypical presentations of AD should be considered in the clinical differential diagnosis of early-onset dementia. Show more

Keywords: Alzheimer's disease, clinical presentation, dementia, early onset

DOI: 10.3233/JAD-2010-1337

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1401-1408, 2010

Authors: Dance, Amber | Landhuis, Esther | Strobel, Gabrielle

Article Type: Editorial

DOI: 10.3233/JAD-2010-1323

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1409-1415, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-1327

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1417-1419, 2010