The Lack of Accumulation of Senile Plaques or Amyloid Burden in Alzheimerʼs Disease Suggests a Dynamic Balance Between Amyloid Deposition and Resolution

Hyman, Bradley T.; Marzloff, Kristin; Arriagada, Paulina V.

doi:10.1097/00005072-199311000-00006

Cited by 247 publications

(131 citation statements)

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“…In accord with previous observations, we found that the profile of plaque sizes when plotted as a function ofA along a linear axis is far from being Gaussian but instead is skewed to the right (13,24,25) (Fig. 2a).…”

Section: Methodssupporting

confidence: 92%

“…The tissue used in this study was 50-,um sections of the temporal lobe that were immunostained with antibody 10D5 (19), a monoclonal antibody directed against A,B. A Bioquant image analysis system was used to semiautomatically assess SP number and cross-sectional area (13), from which the size distribution of plaques was calculated (Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…Operator editing was used to remove artifacts and vesselassociated AP3 deposits and to separate touching structures (4,13).…”

Section: Methodsmentioning

confidence: 99%

“…Although the exact relationship between deposition of A,B and dementia remains uncertain (12)(13)(14), clinical studies in trisomy 21/AD and in apoE e4/AD show that there is increased deposition of A,B in both instances (4,15,16). We have now applied tools derived from the study of polymer formation (17) to study the morphogenesis of SPs, particularly with regard to possible genetic influences.…”

mentioning

confidence: 99%

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Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).

Hyman

West

Rebeck

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

194

105

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The discovery that the E4 allele of the apolipoprotein E (apoE) gene is a putative risk factor for Alzheimer disease (AD) in the general population has highlighted the role of genetic influences in this extremely common and disabling illness. It has long been recognized that another genetic abnormality, trisomy 21 (Down syndrome), is associated with early and severe development of AD neuropathological lesions. It remains a challenge, however, to understand how these facts relate to the pathological changes in the brains of AD patients. We used computerized image analysis to examine the size distribution of one of the characteristic neuropathological lesions in AD, deposits of AP3 peptide in senile plaques (SPs). Surprisingly, we find that a log-normal distribution fits the SP size distribution quite well, motivating a porous model of SP morphogenesis. We then analyzed SP size distribution curves in genotypically defined subgroups of AD patients. The data demonstrate that both apoE £4/AD and trisomy 21/AD lead to increased amyloid deposition, but by apparently different mechanisms. The size distribution curve is shifted toward larger plaques in trisomy 21/AD, probably reflecting increased AP production. In apoE £4/AD, the size distribution is unchanged but the number of SP is increased compared to apoE E3, suggesting increased probability of SP initiation. These results demonstrate that subgroups of AD patients defined on the basis of molecular characteristics have quantitatively different neuropathological phenotypes.

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Section: Methodssupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

“…Operator editing was used to remove artifacts and vesselassociated AP3 deposits and to separate touching structures (4,13).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).

Hyman

West

Rebeck

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

194

105

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“…By contrast, Hyman et al [65] found no quantitative measure of Aβ correlated with age in control patients, or with disease duration in AD, and suggested that Aβ did not accumulate in the brain throughout the course of the disease. That the relationship between SP and NFT and dementia is more complex was also emphasised by Bennett et al [21].…”

Section: Correlation Of Classical Pathology With Clinical Dementiamentioning

confidence: 91%

A critical analysis of the ‘amyloid cascade hypothesis’

Armstrong¹

2014

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A b s t r a c t The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Aβ and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Aβ and tau could be the products rather than the cause of neurodegeneration in AD, (2) it is doubtful whether there is a direct causal link between Aβ and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving

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