Amyloid β peptide ratio 42/40 but not Aβ42 correlates with phospho‐Tau in patients with low‐ and high‐CSF Aβ40 load

Wiltfang, Jens; Esselmann, Hermann; Bibl, Mirko; Hüll, Michael; Hampel, Harald; Kessler, Holger; Frölich, Lutz; Schröder, Johannes; Peters, Oliver; Jessen, Frank; Luckhaus, Christian; Perneczky, Robert; Jahn, Holger; Fiszer, Magdalena; Maler, Juan Manuel; Zimmermann, R; Bruckmoser, Ralf; Kornhuber, Johannes; Lewczuk, Piotr

doi:10.1111/j.1471-4159.2006.04404.x

Cited by 234 publications

(174 citation statements)

References 37 publications

(74 reference statements)

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“…Most abundant Aß peptides in CSF are, in increasing order concentrations, Aß 40 , Aß 38 and Aß 42 (Wiltfang, Esselmann et al 2002). Concentration measurements of the major form Aß 40 in CSF are greatly instructive because they well reflect total amount of Aß peptide release in this biological fluid (Wiltfang, Esselmann et al 2007). By the APP metabolism and the amyloidogenic way, strong cerebral producers of Aß peptides have higher Aß CSF levels (and thus also Aß 42 ) than weak producers.…”

Section: Which Csf Biochemical Markers Might Allow Us To Detect Alzhementioning

confidence: 99%

Alzheimer’s Diseases: Towards Biomarkers for an Early Diagnosis

Elmoualij¹,

Dupiereux-Fettweis²,

Seguin³

et al. 2011

The Clinical Spectrum of Alzheimer's Disease -the Charge Toward Comprehensive Diagnostic and Therapeutic Strategies

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Section: Which Csf Biochemical Markers Might Allow Us To Detect Alzhementioning

confidence: 99%

Alzheimer’s Diseases: Towards Biomarkers for an Early Diagnosis

Elmoualij¹,

Dupiereux-Fettweis²,

Seguin³

et al. 2011

The Clinical Spectrum of Alzheimer's Disease -the Charge Toward Comprehensive Diagnostic and Therapeutic Strategies

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“…Animal models and in vitro cell culture studies have shown that, in most instances, FAD mutations enhance total A␤ production, promote its aggregation and brain deposition, and/or alter the A␤40/A␤42 ratio in favor of A␤42 production (28 -30). Recent studies in human subjects also highlight the importance of A␤40/A␤42 ratio, rather than the total concentration of A␤, as an important biomarker for AD progression and disease severity (31)(32)(33). To evaluate the consequences of altering the ratio A␤40/A␤42, several groups have investigated the effect of co-expressing the two A␤ variants (A␤40 and A␤42) or altering the expression level of one or the other variant in cellular and animal models of AD.…”

mentioning

confidence: 99%

The Ratio of Monomeric to Aggregated Forms of Aβ40 and Aβ42 Is an Important Determinant of Amyloid-β Aggregation, Fibrillogenesis, and Toxicity

Jan

Gökçe

Lüthi-Carter

et al. 2008

Journal of Biological Chemistry

251

235

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Aggregation and fibril formation of amyloid-␤ (A␤) peptides A␤40 and A␤42 are central events in the pathogenesis of Alzheimer disease. Previous studies have established the ratio of A␤40 to A␤42 as an important factor in determining the fibrillogenesis, toxicity, and pathological distribution of A␤. To better understand the molecular basis underlying the pathologic consequences associated with alterations in the ratio of A␤40 to A␤42, we probed the concentration-and ratio-dependent interactions between well defined states of the two peptides at different stages of aggregation along the amyloid formation pathway. We report that monomeric A␤40 alters the kinetic stability, solubility, and morphological properties of A␤42 aggregates and prevents their conversion into mature fibrils. A␤40, at approximately equimolar ratios (A␤40/A␤42 ϳ 0.5-1), inhibits (>50%) fibril formation by monomeric A␤42, whereas inhibition of protofibrillar A␤42 fibrillogenesis is achieved at lower, substoichiometric ratios (A␤40/A␤42 ϳ 0.1). The inhibitory effect of A␤40 on A␤42 fibrillogenesis is reversed by the introduction of excess A␤42 monomer. Additionally, monomeric A␤42 and A␤40 are constantly recycled and compete for binding to the ends of protofibrillar and fibrillar A␤ aggregates. Whereas the fibrillogenesis of both monomeric species can be seeded by fibrils composed of either peptide, A␤42 protofibrils selectively seed the fibrillogenesis of monomeric A␤42 but not monomeric A␤40. Finally, we also show that the amyloidogenic propensities of different individual and mixed A␤ species correlates with their relative neuronal toxicities. These findings, which highlight specific points in the amyloid peptide equilibrium that are highly sensitive to the ratio of A␤40 to A␤42, carry important implications for the pathogenesis and current therapeutic strategies of Alzheimer disease.Alzheimer disease is a progressive neurodegenerative disorder characterized by age-related accumulation of amyloid-␤ (A␤) 2 proteins in the form of diffuse and neuritic plaques in regions of the brain that are affected by the disease (1-4). The discovery of A␤ fibrils as principal constituents of amyloid plaques led to the emergence of the amyloid hypothesis, which implicates the aggregation of A␤ as the primary trigger for a cascade of pathogenic events culminating in neurodegeneration and development of AD (1, 5-7). A␤ proteins are produced in neuronal and non-neuronal cells as a result of sequential proteolytic cleavage of the type I transmembrane amyloid precursor protein (APP) by ␤-and ␥-secretases (8 -12). Depending on the site of APP cleavage by ␥-secretase, A␤ proteins of various chain lengths are generated (13-16). The predominant A␤ species in human plasma and CSF, as well as in conditioned media of APP-expressing cells, is A␤40 (ϳ90%) followed by A␤42 (ϳ10%). Despite the preponderance of A␤40, in vivo studies reveal that A␤42 is a major constituent of amyloid plaques and suggest that A␤42 aggregation plays a critical role in the initiation of plaque f...

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“…A reduced level of Beta-amyloid has also been reported in the CSF of patients with sporadic CJD when compared to control samples [68]. These CSF biomarkers have proven to be an extremely valuable in the confirmatory diagnosis of CJD cases.…”

Section: Alpha-synuclein and Beta-amyloidmentioning

confidence: 89%