The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer's disease.
We have utilised laser confocal microscopy to categorise beta-amyloid plaque types that are associated with preclinical and end-stage Alzheimer's disease and to define the neurochemistry of dystrophic neurites associated with various forms of plaques. Plaques with a spherical profile were defined as either diffuse, fibrillar or dense-cored using Thioflavin S staining or immunolabelling for beta-amyloid. Confocal analysis demonstrated that fibrillar plaques had a central mass of beta-amyloid with compact spoke-like extensions leading to a confluent outer rim. Dense-cored plaques had a compacted central mass surrounded by an outer sphere of beta-amyloid. Diffuse plaques lacked a morphologically identifiable substructure, resembling a ball of homogeneous labelling. The relative proportion of diffuse, fibrillar and dense-cored plaques was 53, 22 and 25% in preclinical and 31, 49 and 20% in end-stage Alzheimer's disease cases, respectively. Plaque-associated dystrophic neurites in preclinical cases were immunolabeled for neurofilament proteins whereas, in end-stage cases, these abnormal neurites were variably labelled for tau and/or neurofilaments. Double labelling demonstrated that the proportion of diffuse, fibrillar and dense-cored plaques that were neuritic was 12, 47 and 82% and 24, 82 and 76% in preclinical and end-stage cases, respectively. Most dystrophic neurites in Alzheimer's disease cases were labelled for either neurofilaments or tau, however, confocal analysis determined that 30% of neurofilament-labelled bulb-like or elongated neurites had a core of tau immunoreactivity. These results indicate that all morphologically defined beta-amyloid plaque variants were present in both early and late stages of Alzheimer's disease. However, progression to clinical dementia was associated with both a shift to a higher proportion of fibrillar plaques that induced local neuritic alterations and a transformation of cytoskeletal proteins within associated abnormal neuronal processes. There data indicate key pathological changes that may be subject to therapeutic intervention to slow the progression of Alzheimer's disease.
Dickson
T C
TC
Discipline of Pathology, Clinical School, University of Tasmania, 43 Collins St, 7000, Hobart, Tasmania, Australia.
Vickers
J C
JC
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D052160:Benzothiazoles; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D016501:Neurites / Q000378:metabolism / Q000473:pathology*; D016900:Neurofilament Proteins / Q000378:metabolism; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D013844:Thiazoles / Q000493:pharmacokinetics; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D016900:Neurofilament Proteins; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T