Role of water‐soluble amyloid‐β in the pathogenesis of Alzheimer's disease

Tabaton, Massimo; Piccini, Alessandra

doi:10.1111/j.0959-9673.2005.00428.x

Cited by 47 publications

(25 citation statements)

References 52 publications

(77 reference statements)

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“…Russo et al (77) showed that cases with a PS1 mutation developed a higher ratio of water-soluble A␤ pE3-42 and A␤ pE11-42 to full-length A␤ in comparison with sporadic AD cases. In line with this observation, water-soluble A␤ from brains of normal elderly individuals with abundant amyloid and neurofibrillary pathology demonstrated a decreased A␤ pE3-42 /A␤ 1-42 ratio compared with AD cases (76). Overall, the ratio of watersoluble A␤ pE3-42 to A␤ seems to be proportional to the clinical phenotype and the severity of the disease.…”

Section: Soluble Oligomeric Pyroglutamate A␤: the Missing Link In A␤ supporting

confidence: 65%

“…In DS, water-soluble A␤ appeared early (ϳ20 years before the appearance of the plaques) and increased with age and the progression of the amyloid pathology. Interestingly, water-soluble A␤ increased by 100-fold in young cases accompanied by an increase in A␤ pE3-42 (76). Russo et al (77) showed that cases with a PS1 mutation developed a higher ratio of water-soluble A␤ pE3-42 and A␤ pE11-42 to full-length A␤ in comparison with sporadic AD cases.…”

Section: Soluble Oligomeric Pyroglutamate A␤: the Missing Link In A␤ mentioning

confidence: 99%

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Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Jawhar

Wirths

Bayer

2011

Journal of Biological Chemistry

195

225

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Pyroglutamate-modified amyloid-␤ (A␤ pE3 ) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of A␤ pE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of A␤ pE3 . In this minireview, we summarize the current knowledge on A␤ pE3 , discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.When Alois Alzheimer presented the case of his patient Auguste Deter at the Tübingen meeting of the Southwest German Psychiatrists in 1906, he did not attract much attention or stimulate any discussion in the audience. The young doctor likely would not have believed that, 100 years later, the disease that now holds his name would be the most common cause of dementia and a source of a critical medical and economical problem. At this meeting, Alzheimer presented Auguste Deter's symptoms and reported the histopathological features that are now associated with Alzheimer disease (AD) 2 : neuron loss, extracellular amyloid plaques, and intracellular neurofibrillary tangles. For more than 2 decades, the amyloid hypothesis has been the cardinal hypothesis in describing the sequence of AD etiology. The amyloid hypothesis considers amyloid-␤ (A␤) deposition to be the causative event of AD pathology and that neurofibrillary tangles, cell loss, vascular damage, and dementia occur as a consequence of it (1). However, it has been recently suggested that the extracellular formation of A␤ plaques and other AD pathological events are preceded by intraneuronal A␤ accumulation, giving rise to a modified amyloid hypothesis (2).The story of successful discoveries in modern AD research using novel molecular biological tools started with the biochemical analysis of ␤-amyloid-containing blood vessels (congophilic amyloid angiopathy) (3) and amyloid plaques consisting of A␤ (4), which led to the isolation and sequencing of the gene encoding the larger amyloid precursor protein (APP) (5, 6).In vitro and in vivo analyses of amyloid deposits in AD revealed various N-and C-terminal variants (4, 7, 8). Increased C-terminal length of A␤ (from A␤ x-40 to A␤ x-42 ) in AD enhanced aggregation and early deposition and promoted the toxicity of A␤ (9 -11). Recently, A␤ 1-43 has been discussed as a novel toxic peptide in AD (12).Beside A␤ peptides, starting with aspartate as the first amino acid (A␤ 1-x ), several N-terminally truncated and modified A␤ species have been described (4, 13-15). Among A␤ species present in AD plaques, Lewis et al. (16) reported that A␤ 4 -42 is a relatively abundant species in AD, aged control, and vascular dementia patients. Using immunoprecipitation in combination with mass spectrome...

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Section: Soluble Oligomeric Pyroglutamate A␤: the Missing Link In A␤ supporting

confidence: 65%

Section: Soluble Oligomeric Pyroglutamate A␤: the Missing Link In A␤ mentioning

confidence: 99%

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Jawhar

Wirths

Bayer

2011

Journal of Biological Chemistry

195

225

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“…Others have found in cultured cells intracellular A␤ accumulation derived from the Golgi network and endoplasmic reticulum (18,(22)(23)(24)(25)(26). Piccini et al (27), using immunoprecipitation, have identified A␤ species in soluble extracts of frozen AD and control brain (27,28), but did not examine for tau complexes. Lue et al (29) detected, by ELISA, A␤40 and A␤42 in soluble extracts of frozen entorhinal and superior frontal cortex from AD cases, high pathology controls, and normal controls with AD cases showing the highest level of both A␤ species.…”

Section: Discussionmentioning

confidence: 99%

Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

Jian-ping

Arai

Miklóssy

et al. 2006

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

219

202

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To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-␤ protein (A␤). This complex enhances tau phosphorylation by GSK3␤, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. A␤ binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple A␤ peptides in the mid to C-terminal regions of A␤. This binding is also significantly decreased by GSK3␤ phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of A␤ for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected A␤ bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and A␤ form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble A␤ to soluble nonphosphorylated tau, thus promoting tau phosphorylation and A␤ nucleation. Blocking the sites where A␤ initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.immunochemistry ͉ neurofibrillary tangles ͉ senile plaques ͉ surface plasmon resonance S o far, no reasonable interpretation has been advanced to explain the simultaneous appearance of senile plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Senile plaques develop extracellularly with the main component being aggregated amyloid-␤ protein (A␤), whereas NFTs develop intracellularly with the main component being aggregated forms of phosphorylated tau. The two aggregation processes appear to occur independently, because NFTs develop in neuronal cell bodies and senile plaques develop around their nerve endings. This observation has led to two schools of thought regarding AD causation. The tau hypothesis holds that the disease is driven by tangles resulting from an excess of tau phosphorylation or a deficiency of its dephosphorylation (1). The hypothesis does not explain plaques. The amyloid hypothesis holds that the disease is driven by excess production of A␤ (2, 3). This hypothesis does not explain NFTs. Nevertheless, the amyloid cascade hypothesis is dominant because mutations in amyloid precursor protein (APP), which enhance A␤ production, cause autosomal dominant AD but not other types of dementia (2). On the other hand, mutations in tau that promote tau aggregation produce autosomal dominant frontotemporal dementia but not AD (4, 5). As a result, the presumption is that excess A␤ is a major cause and an upstream event of AD tangle formation, but exactly how an A␤ excess ...

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“…Indeed, fluvastatin significantly increased A␤ clearance rate at an injected concentration of 10 M (Fig. 6C), whereas it failed to affect A␤ clearance rate at 20 nM and 1 M. As the injected drug was diluted at least 30-fold by diffusion immediately after administration and spread farther (42) and the soluble A␤ level in the brain of AD patients is near or over 100 nM (43)(44)(45), our present study might be relevant in the pathological state of AD rather than in the normal physiological state (physiolog- ical A␤ level is about 1 nM). Because we previously showed that fluvastatin did not affect the activity and level of major A␤-degrading enzymes such as neprilysin and insulin-degrading enzyme in the brain (25), we focused on the levels of apolipoprotein E, P-glycoprotein and the low density lipoproteinrelated protein 1 (LRP1), which are reported to be involved in A␤ clearance from the brain (46).…”

Section: Figure 2 Effects Of Lysosomal Inhibitors On Reduction Of Apmentioning

confidence: 91%

Reduction of Brain β-Amyloid (Aβ) by Fluvastatin, a Hydroxymethylglutaryl-CoA Reductase Inhibitor, through Increase in Degradation of Amyloid Precursor Protein C-terminal Fragments (APP-CTFs) and Aβ Clearance

Shinohara

Sato

Kurinami

et al. 2010

Journal of Biological Chemistry

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Epidemiological studies suggest that statins (hydroxymethylglutaryl-CoA reductase inhibitors) could reduce the risk of Alzheimer disease. Although one possible explanation is through an effect on ␤-amyloid (A␤) metabolism, its effect remains to be elucidated. Here, we explored the molecular mechanisms of how statins influence A␤ metabolism. Fluvastatin at clinical doses significantly reduced A␤ and amyloid precursor protein C-terminal fragment (APP-CTF) levels among APP metabolites in the brain of C57BL/6 mice. Chronic intracerebroventricular infusion of lysosomal inhibitors blocked these effects, indicating that up-regulation of the lysosomal degradation of endogenous APP-CTFs is involved in reduced A␤ production. Biochemical analysis suggested that this was mediated by enhanced trafficking of APP-CTFs from endosomes to lysosomes, associated with marked changes of Rab proteins, which regulate endosomal function. In primary neurons, fluvastatin enhanced the degradation of APP-CTFs through an isoprenoid-dependent mechanism. Because our previous study suggests additive effects of fluvastatin on A␤ metabolism, we examined A␤ clearance rates by using the brain efflux index method and found its increased rates at high A␤ levels from brain. As LRP1 in brain microvessels was increased, up-regulation of LRP1-mediated A␤ clearance at the blood-brain barrier might be involved. In cultured brain microvessel endothelial cells, fluvastatin increased LRP1 and the uptake of A␤, which was blocked by LRP1 antagonists, through an isoprenoid-dependent mechanism. Overall, the present study demonstrated that fluvastatin reduced A␤ level by an isoprenoid-dependent mechanism. These results have important implications for the development of disease-modifying therapy for Alzheimer disease as well as understanding of A␤ metabolism. Alzheimer disease (AD)2 is a progressive neurodegenerative disease, being the most prevalent disorder among dementia. The discoveries that the genes of familial AD-linked mutation up-regulate A␤ production and the increased rate of A␤42 production is associated with the age of onset provide conclusive evidence for the amyloid hypothesis in the pathogenesis of AD (1). Several therapies based on the amyloid hypothesis are being examined, including ␥-secretase inhibitors and A␤ vaccine therapy, as disease-modifying therapy. However, there are still many unresolved issues with their clinical application (2, 3). Furthermore, recent failures of clinical trials of these therapies raise questions on delayed timing of intervention and the efficacy of targeting only one pathway of A␤ metabolism (4, 5). More efficient treatment with higher safety is needed to treat AD.On the other hand, from basic and clinical reports, statins (hydroxymethylglutaryl-CoA reductase inhibitors), which are widely used for the treatment of hypercholesterolemic patients, might be beneficial in AD. Clinically, many case control studies support the protective effect of statins (6 -8), whereas the results of prospective studies and randomized cli...

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Role of water‐soluble amyloid‐β in the pathogenesis of Alzheimer's disease

Cited by 47 publications

References 52 publications

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Aβ and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease

Reduction of Brain β-Amyloid (Aβ) by Fluvastatin, a Hydroxymethylglutaryl-CoA Reductase Inhibitor, through Increase in Degradation of Amyloid Precursor Protein C-terminal Fragments (APP-CTFs) and Aβ Clearance

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