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The pathogenic aβ43 is enriched in familial and sporadic Alzheimer disease.

Sandebring A, Welander H, Winblad B, Graff C, Tjernberg LO - PLoS ONE (2013)

Bottom Line: Levels of Aβ43, as well as Aβ40 and Aβ42, were quantified using ELISA.We compared quantitative data showing Aβ levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls.Results showed Aβ43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, KI-Alzheimer's Disease Research center (KI-ADRC), Huddinge, Sweden.

ABSTRACT
The amyloid-cascade hypothesis posits that the role of amyloid β-peptide (Aβ) in Alzheimer disease (AD) involves polymerization into structures that eventually are deposited as amyloid plaques. During this process, neurotoxic oligomers are formed that induce synaptic loss and neuronal death. Several different isoforms of Aβ are produced, of which the 40 and 42 residue variants (Aβ40 and Aβ42) are the most common. Aβ42 has a strong tendency to form neurotoxic aggregates and is involved in AD pathogenesis. Longer Aβ isoforms, like the less studied Aβ43, are gaining attention for their higher propensity to aggregate into neurotoxic oligomers. To further investigate Aβ43 in AD, we conducted a quantitative study on Aβ43 levels in human brain. We homogenized human brain tissue and prepared fractions of various solubility; tris buffered saline (TBS), sodium dodecyl sulfate (SDS) and formic acid (FA). Levels of Aβ43, as well as Aβ40 and Aβ42, were quantified using ELISA. We compared quantitative data showing Aβ levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls. Results showed Aβ43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases. Aβ42 and Aβ43 were enriched in the less soluble fractions (SDS and FA) of SAD and FAD cases in both occipital and frontal cortex. Thus, although the total levels of Aβ43 in human brain are low compared to Aβ40 and Aβ42, we suggest that Aβ43 could initiate the formation of oligomers and amyloid plaques and thereby be crucial to AD pathogenesis.

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Scatter plots representing the enrichment of Aβ40, Aβ42 and Aβ43 in human brain.Absolute levels of Aβ in SDS-soluble and FA-soluble fractions were divided by levels in TBS-soluble fractions. ND: non-demented; SAD: sporadic Alzheimer disease; FAD: familial Alzheimer disease. a) Enrichment of insoluble Aβ in human frontal cortex; b) Enrichment of insoluble Aβ in human occipital cortex. *<0.05; **<0.01; #<0.05; ##<0.01.
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pone-0055847-g005: Scatter plots representing the enrichment of Aβ40, Aβ42 and Aβ43 in human brain.Absolute levels of Aβ in SDS-soluble and FA-soluble fractions were divided by levels in TBS-soluble fractions. ND: non-demented; SAD: sporadic Alzheimer disease; FAD: familial Alzheimer disease. a) Enrichment of insoluble Aβ in human frontal cortex; b) Enrichment of insoluble Aβ in human occipital cortex. *<0.05; **<0.01; #<0.05; ##<0.01.

Mentions: The ratio between the insoluble fractions (SDS+FA) and TBS soluble (TBS) was calculated in order to analyze the potential enrichment of the different Aβ species in the less soluble fractions. We presumed that the more hydrophobic and, thereby, more aggregation prone peptides, Aβ42 and Aβ43, would be more enriched in the SAD and FAD groups than in the ND group. Indeed, Aβ42 and Aβ43 were similarly enriched in the SDS and FA fractions in both frontal and occipital cortex from SAD and FAD, while no such changes were observed for Aβ40 (Fig. 5a and 5b). These results are in line with the notion that Aβ40 is less prone to form neurotoxic aggregates than Aβ42 and Aβ43. The intra-individual differences were large in the SAD group, whereas most ND cases showed low enrichment of all the Aβ isoforms analyzed. In frontal cortex, we found that the enrichment of Aβ42 and Aβ43 was elevated in SAD compared to ND, and that Aβ43 was also increased in FAD compared to ND. In occipital cortex, Aβ42 enrichment was increased in both SAD and FAD compared to ND, while Aβ43 was increased only in the SAD group. The variation among cases may reflect disease severity, high enrichment indicating an advanced disease stage. In line with this theory, quantitative results from occipital cortex of both probable and possible AD cases included in the SAD group were in the lower range.


The pathogenic aβ43 is enriched in familial and sporadic Alzheimer disease.

Sandebring A, Welander H, Winblad B, Graff C, Tjernberg LO - PLoS ONE (2013)

Scatter plots representing the enrichment of Aβ40, Aβ42 and Aβ43 in human brain.Absolute levels of Aβ in SDS-soluble and FA-soluble fractions were divided by levels in TBS-soluble fractions. ND: non-demented; SAD: sporadic Alzheimer disease; FAD: familial Alzheimer disease. a) Enrichment of insoluble Aβ in human frontal cortex; b) Enrichment of insoluble Aβ in human occipital cortex. *<0.05; **<0.01; #<0.05; ##<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569467&req=5

pone-0055847-g005: Scatter plots representing the enrichment of Aβ40, Aβ42 and Aβ43 in human brain.Absolute levels of Aβ in SDS-soluble and FA-soluble fractions were divided by levels in TBS-soluble fractions. ND: non-demented; SAD: sporadic Alzheimer disease; FAD: familial Alzheimer disease. a) Enrichment of insoluble Aβ in human frontal cortex; b) Enrichment of insoluble Aβ in human occipital cortex. *<0.05; **<0.01; #<0.05; ##<0.01.
Mentions: The ratio between the insoluble fractions (SDS+FA) and TBS soluble (TBS) was calculated in order to analyze the potential enrichment of the different Aβ species in the less soluble fractions. We presumed that the more hydrophobic and, thereby, more aggregation prone peptides, Aβ42 and Aβ43, would be more enriched in the SAD and FAD groups than in the ND group. Indeed, Aβ42 and Aβ43 were similarly enriched in the SDS and FA fractions in both frontal and occipital cortex from SAD and FAD, while no such changes were observed for Aβ40 (Fig. 5a and 5b). These results are in line with the notion that Aβ40 is less prone to form neurotoxic aggregates than Aβ42 and Aβ43. The intra-individual differences were large in the SAD group, whereas most ND cases showed low enrichment of all the Aβ isoforms analyzed. In frontal cortex, we found that the enrichment of Aβ42 and Aβ43 was elevated in SAD compared to ND, and that Aβ43 was also increased in FAD compared to ND. In occipital cortex, Aβ42 enrichment was increased in both SAD and FAD compared to ND, while Aβ43 was increased only in the SAD group. The variation among cases may reflect disease severity, high enrichment indicating an advanced disease stage. In line with this theory, quantitative results from occipital cortex of both probable and possible AD cases included in the SAD group were in the lower range.

Bottom Line: Levels of Aβ43, as well as Aβ40 and Aβ42, were quantified using ELISA.We compared quantitative data showing Aβ levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls.Results showed Aβ43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, KI-Alzheimer's Disease Research center (KI-ADRC), Huddinge, Sweden.

ABSTRACT
The amyloid-cascade hypothesis posits that the role of amyloid β-peptide (Aβ) in Alzheimer disease (AD) involves polymerization into structures that eventually are deposited as amyloid plaques. During this process, neurotoxic oligomers are formed that induce synaptic loss and neuronal death. Several different isoforms of Aβ are produced, of which the 40 and 42 residue variants (Aβ40 and Aβ42) are the most common. Aβ42 has a strong tendency to form neurotoxic aggregates and is involved in AD pathogenesis. Longer Aβ isoforms, like the less studied Aβ43, are gaining attention for their higher propensity to aggregate into neurotoxic oligomers. To further investigate Aβ43 in AD, we conducted a quantitative study on Aβ43 levels in human brain. We homogenized human brain tissue and prepared fractions of various solubility; tris buffered saline (TBS), sodium dodecyl sulfate (SDS) and formic acid (FA). Levels of Aβ43, as well as Aβ40 and Aβ42, were quantified using ELISA. We compared quantitative data showing Aβ levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls. Results showed Aβ43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases. Aβ42 and Aβ43 were enriched in the less soluble fractions (SDS and FA) of SAD and FAD cases in both occipital and frontal cortex. Thus, although the total levels of Aβ43 in human brain are low compared to Aβ40 and Aβ42, we suggest that Aβ43 could initiate the formation of oligomers and amyloid plaques and thereby be crucial to AD pathogenesis.

Show MeSH
Related in: MedlinePlus