A Comparison of β-Amyloid Deposition in the Medial Temporal Lobe in Sporadic Alzheimer's Disease, Down's Syndrome and Normal Elderly Brains

Armstrong, Richard A.; Cairns, Nigel J.; Myers, D.; Smith, C. U. M.; Rossor, Martin N.

doi:10.1006/neur.1996.0005

Cited by 19 publications

(12 citation statements)

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“…In particular, although debated until now, neurofibrillary tangles composed of hyperphosphorylated protein tau are considered a secondary event in the disease progression, a consequence of Aβ toxicity and Aβ plaque formation (Verdile et al, 2004). Amyloid plaques, one of the defining neuropathological characteristics of AD, are neither specific of this condition (Armstrong et al, 1996, Dickson et al, 1992, Yamaguchi et al, 1998) nor are properly “pathogenic”, as they have now come to be considered an end stage of amyloid deposition, representing an inactive reservoirs of species that are in equilibrium with the smaller, putatively neurotoxic assemblies (Hardy and Selkoe, 2002). Although neuronal degeneration occurs in proximity of the amyloid plaques, some studies have suggested that intermediate Aβ aggregates such as protofibrils or simple oligomers are also involved in AD pathogenesis and even appear to be the more dangerous species.…”

Section: Amyloid-β: Functions and Dysfunctionsmentioning

confidence: 99%

Signaling effect of amyloid-β42 on the processing of AβPP

Tabaton

Zhu

Perry

et al. 2010

Experimental Neurology

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The effects of amyloid-β are extremely complex. Current work in the field of Alzheimer disease is focusing on discerning the impact between the physiological signaling effects of soluble low molecular weight amyloid-β species, and the more global cellular damage that could derive from highly concentrated and/or aggregated amyloid. Being able to dissect the specific signaling events, to understand how soluble amyloid-β induces its own production by upregulating BACE1 expression, could lead to new tools to interrupt the distinctive feedback cycle with potential therapeutic consequences. Here we describe a positive loop that exists between the secretases that are responsible for the generation of the amyloid-β component of Alzheimer disease. According to our hypothesis, in familial Alzheimer disease, the primary overproduction of amyloid-β can induce BACE1 transcription and drive a further increase of amyloid-β precursor protein processing and resultant amyloid-β production. In sporadic Alzheimer disease, many factors, among them oxidative stress and inflammation, with consequent induction of presenilins and BACE1, would activate a loop and proceed with the generation of amyloid-β and its signaling role onto BACE1 transcription. This concept of a signaling effect by and feedback on the amyloid-β precursor protein will likely shed light on how amyloid-β generation, oxidative stress, and secretase functions are intimately related in sporadic Alzheimer disease.

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Section: Amyloid-β: Functions and Dysfunctionsmentioning

confidence: 99%

Signaling effect of amyloid-β42 on the processing of AβPP

Tabaton

Zhu

Perry

et al. 2010

Experimental Neurology

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“…13,15 On the contrary, in normal elderly subjects with abundant amyloid deposition in frontal cortex and absence of signs of neuronal degeneration and dementia, the main component of WSAb is the full-length peptide Ab1-42. 8,[18][19][20][21] This suggests that the ratio of soluble Ab species may dictate the toxicity of the aggregates. In fact, the toxic effect of WSAb on neurons seems to be related to the predominance of N-terminal truncated Abpy3-42 peptide.…”

Section: Introductionmentioning

confidence: 97%

N‐terminal truncated pyroglutamyl β amyloid peptide Aβpy3‐42 shows a faster aggregation kinetics than the full‐length Aβ1‐42

2009

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We tested directly the differences in the aggregation kinetics of three important beta amyloid peptides, the full-length Abeta1-42, and the two N-terminal truncated and pyroglutamil modified Abetapy3-42 and Abetapy11-42 found in different relative concentrations in the brains in normal aging and in Alzheimer disease. By following the circular dichroism signal and the ThT fluorescence of the solution in phosphate buffer, we found substantially faster aggregation kinetics for Abetapy3-42. This behavior is due to the particular sequence of this peptide, which is also responsible for the specific oligomeric aggregation states, found by TEM, during the fibrillization process, which are very different from those of Abeta1-42, more prone to fibril formation. In addition, Abetapy3-42 is found here to have an inhibitory effect on Abeta1-42 fibrillogenesis, coherently with its known greater infective power. This is an indication of the important role of this peptide in the aggregation process of beta-peptides in Alzheimer disease.

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“…In DS brains, increased oxidative damage occurs prior to the onset of Aβ deposition (Nunomura et al ., 2000), although APP protein levels are several times higher than expected from trisomy 21 gene dosage (Oyama et al ., 1994). Moreover, no mutation in the APP gene has been found in DS patients yet numerous diffuse plaques containing full‐length APP were observed (Armstrong et al ., 1996; Egensperger et al ., 1999).…”

Section: Introductionmentioning

confidence: 99%

Functional and morphological alterations in compound transgenic mice overexpreszing Cu/Zn superoxide dismutaze and amyloid precursor protein

Harris-Cerruti

Kamsler

Kaplan

et al. 2004

Eur J of Neuroscience

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Down's syndrome (DS), the phenotypic manifestation of trisomy 21, involves overexpression of chromosome 21-encoded genes. The gene for amyloid precursor protein (APP), known to be involved in AD pathology, resides on chromosome 21 along with the gene for Cu/Zn superoxide dismutase (SOD1), a key enzyme in the metabolism of oxygen free radicals. We investigated the consequences of a combined increase in APP and SOD1, in a double-transgenic (tg)-APP-SOD1 mouse. These mice expressed severe impairment in learning, working and long-term memory. Expression of long-term potentiation in hippocampal slices was impaired in both tg-SOD and tg-APP-SOD mice, but not in tg-APP mice, indicating that increased APP by itself did not affect in vitro synaptic plasticity. In tg-APP-SOD mice, membrane-bound high molecular weight APP species accumulated while APP cleavage products did not increase and levels of secreted APP were unchanged. Severe morphological damage, including lipofuscin accumulation and mitochondria abnormalities, were found in aged tg-APP-SOD but not in the other mice. Thus, a combined elevation of the two chromosome 21 genes in tg-APP-SOD mice induced age-dependent alterations in morphological and behavioural functions.

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A Comparison of β-Amyloid Deposition in the Medial Temporal Lobe in Sporadic Alzheimer's Disease, Down's Syndrome and Normal Elderly Brains

Cited by 19 publications

References 0 publications

Signaling effect of amyloid-β42 on the processing of AβPP

Signaling effect of amyloid-β42 on the processing of AβPP

N‐terminal truncated pyroglutamyl β amyloid peptide Aβpy3‐42 shows a faster aggregation kinetics than the full‐length Aβ1‐42

Functional and morphological alterations in compound transgenic mice overexpreszing Cu/Zn superoxide dismutaze and amyloid precursor protein

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