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Cytoskeletal alterations differentiate presenilin-1 and sporadic Alzheimer's disease

Citation

Woodhouse, A and Shepherd, CE and Sokolova, A and Carroll, VL and King, AE and Halliday, GM and Dickson, TC and Vickers, JC, Cytoskeletal alterations differentiate presenilin-1 and sporadic Alzheimer's disease, Acta Neuropathologica, 117, (1) pp. 19-29. ISSN 0001-6322 (2009) [Refereed Article]

DOI: doi:10.1007/s00401-008-0458-z

Abstract

Most cases of Alzheimer’s disease (AD) are sporadic in nature, although rarer familial AD (FAD) cases have provided important insights into major pathological disease mechanisms. Mutations in the presenilin 1 gene (PS1) are responsible for the majority of FAD cases, causing an earlier age of onset and more rapid progression to end-stage disease than seen in sporadic AD. We have investigated the cytoskeletal alterations in neuritic AD pathology in a cohort of FAD cases in comparison to sporadic AD and pathologically aged cases. Tau-immunoreactive neurofibrillary tangle (NFT) loads were similar between PS1 FAD and sporadic AD cases. Similarly, plaque loads, both B-amyloid (AB) and thio- flavine S, in PS1 FAD and sporadic AD cases were not significantly different; however, in pathologically aged cases, they were significantly lower than those in PS1 cases, but were not different from sporadic AD cases. The ‘cotton wool’ plaque characteristic of PS1 cases did not demonstrate a high density of dystrophic neurites compared to other AB plaque types, but did demonstrate a localised mass effect on the neuropil. Despite minimal differences in plaque and NFT loads, immunolabelling demonstrated clear phenotypic differences in the NFTs and dystrophic neurites in PS1 FAD cases. Presenilin-1 cases exhibited significantly (P < 0.05) more tau-positive NFTs that were immunolabelled by the antibody SMI312 (anti-phosphorylated NF protein and phosphorylated tau) than sporadic AD cases. Presenilin-1 cases also exhibited numerous ring-like NF-positive and elongated taulabelled dystrophic neurites, whereas these dystrophic neurite types were only abundant at the very early (pathologically aged cases) or very late stages of sporadic AD progression, respectively. These differences in cytoskeletal pathology in PS1 cases suggest an accelerated rate of neuritic pathology development, potentially due to mutant PS1 influencing multiple pathogenic pathways.

Item Details

Item Type:Refereed Article
Keywords:Presenilin-1; Familial Alzheimer’s disease; Dystrophic neurites; Neurofibrillary tangles; Cotton wool plaques
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Woodhouse, A (Dr Adele Woodhouse)
Author:Sokolova, A (Ms Anna Sokolova)
Author:Carroll, VL (Miss Vicki Carroll)
Author:King, AE (Associate Professor Anna King)
Author:Dickson, TC (Professor Tracey Dickson)
Author:Vickers, JC (Professor James Vickers)
ID Code:59227
Year Published:2009
Web of Science® Times Cited:16
Deposited By:Menzies Institute for Medical Research
Deposited On:2009-11-26
Last Modified:2010-04-16
Downloads:0

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