title: Cytoskeletal alterations differentiate presenilin-1 and sporadic Alzheimer's disease.
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 beta-amyloid (Abeta) and thioflavine 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 Abeta 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 tau-labelled 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.
authors.affiliation: Wicking Dementia Research and Education Centre and NeuroRepair Group, Menzies Research Institute, Private Bag 29, Hobart, TAS, 7001, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Woodhouse
authors.forename: Claire E
authors.initials: CE
authors.lastname: Shepherd
authors.forename: Anna
authors.initials: A
authors.lastname: Sokolova
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Carroll
authors.forename: Anna E
authors.initials: AE
authors.lastname: King
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.forename: Tracey C
authors.initials: TC
authors.lastname: Dickson
authors.forename: James C
authors.initials: JC
authors.lastname: Vickers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D001344:Autopsy; D052160:Benzothiazoles; D015153:Blotting, Western; D015331:Cohort Studies; D003599:Cytoskeleton / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000378:metabolism*; D012720:Severity of Illness Index; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D053764:Presenilin-1; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T