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Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson's disease.

Swirski M, Miners JS, de Silva R, Lashley T, Ling H, Holton J, Revesz T, Love S - Alzheimers Res Ther (2014)

Bottom Line: In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains.In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn.Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).

View Article: PubMed Central - PubMed

Affiliation: Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.

ABSTRACT

Introduction: Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn.

Methods: We measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson's disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage.

Results: In most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).

Conclusions: Together, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases.

No MeSH data available.


Related in: MedlinePlus

Correlation between Aβ and insolublepSer129 α-syn. Each point represents a separatecase. The best-fit linear regression (solid lines) and 95%confidence intervals (interrupted lines) are superimposed.Only significant P-values(and associated correlation coefficients) are shown in thefigure. Significant positive correlations between insolublepSer129 α-syn and soluble Aβ42/Aβ40 were found in theparahippocampal (PH) cortex and thalamus (TH). Significantpositive correlations were also found between insolublepSer129 α-syn and insoluble Aβ42 in the cingulate (CG) and PHcortex. In addition, significant correlations were foundbetween insoluble pSer129 α-syn and insoluble Aβ40 in themidfrontal and CG cortex. Aβ, amyloid-β; pSer129 α-syn,alpha-synuclein phosphorylated at serine 129.
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Fig1: Correlation between Aβ and insolublepSer129 α-syn. Each point represents a separatecase. The best-fit linear regression (solid lines) and 95%confidence intervals (interrupted lines) are superimposed.Only significant P-values(and associated correlation coefficients) are shown in thefigure. Significant positive correlations between insolublepSer129 α-syn and soluble Aβ42/Aβ40 were found in theparahippocampal (PH) cortex and thalamus (TH). Significantpositive correlations were also found between insolublepSer129 α-syn and insoluble Aβ42 in the cingulate (CG) and PHcortex. In addition, significant correlations were foundbetween insoluble pSer129 α-syn and insoluble Aβ40 in themidfrontal and CG cortex. Aβ, amyloid-β; pSer129 α-syn,alpha-synuclein phosphorylated at serine 129.

Mentions: In most regions the level of insoluble pSer129 α-synincreased as the levels of Aβ40 and Aβ42 increased (Figure 1, Additional file 3: Table S1), with significant positivecorrelations between insoluble pSer129 α-syn and soluble Aβ40 and Aβ42 inthe parahippocampal cortex (soluble Aβ40: r = 0.376, P = 0.003; soluble Aβ42: r = 0.287, P = 0.024) and thalamus (soluble Aβ40: r =0.398, P = 0.002; soluble Aβ42: r =0.404, P = 0.002). Significantpositive correlations were also found between insoluble pSer129 α-syn andinsoluble Aβ42 in the cingulate (r = 0.293, P = 0.022) and parahippocampal cortex (r = 0.314,P = 0.013) as well as betweeninsoluble pSer129 α-syn and insoluble Aβ40 in the midfrontal (r = 0.719,P <0.0001) and cingulate cortex(r = 0.304, P = 0.017). Significantnegative correlations between soluble pSer129 α-syn and soluble Aβ42 werefound in the cingulate cortex and thalamus (Figure 2; Additional file 3: Table S1) (cingulate cortex:r = −0.287, P = 0.035; thalamus:r = −0.373, P = 0.0036). In contrast,a significant positive correlation was observed between soluble Aβ42 andsoluble pSer129 α-syn in the midfrontal cortex (r = 0.443, P = 0.0015). Significant negativecorrelations between soluble Aβ40 and soluble pSer129 α-syn were found inthree of four regions (cingulate cortex: r = −0.313, P = 0.021; parahippocampal cortex:r = −0.286, P = 0.028; and thalamus: r = −0.376, P = 0.0033). Significant negative correlations were alsofound between soluble pSer129 α-syn and insoluble Aβ42 in the midfrontalcortex and thalamus (midfrontal cortex: r = −0.475, P = 0.0005; thalamus: r = −0.399, P = 0.0018). A significant positivecorrelation between soluble pSer129 α-syn and insoluble Aβ40 was alsofound in the parahippocampus (r = 0.316, P = 0.015).Figure 1


Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson's disease.

Swirski M, Miners JS, de Silva R, Lashley T, Ling H, Holton J, Revesz T, Love S - Alzheimers Res Ther (2014)

Correlation between Aβ and insolublepSer129 α-syn. Each point represents a separatecase. The best-fit linear regression (solid lines) and 95%confidence intervals (interrupted lines) are superimposed.Only significant P-values(and associated correlation coefficients) are shown in thefigure. Significant positive correlations between insolublepSer129 α-syn and soluble Aβ42/Aβ40 were found in theparahippocampal (PH) cortex and thalamus (TH). Significantpositive correlations were also found between insolublepSer129 α-syn and insoluble Aβ42 in the cingulate (CG) and PHcortex. In addition, significant correlations were foundbetween insoluble pSer129 α-syn and insoluble Aβ40 in themidfrontal and CG cortex. Aβ, amyloid-β; pSer129 α-syn,alpha-synuclein phosphorylated at serine 129.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4248436&req=5

Fig1: Correlation between Aβ and insolublepSer129 α-syn. Each point represents a separatecase. The best-fit linear regression (solid lines) and 95%confidence intervals (interrupted lines) are superimposed.Only significant P-values(and associated correlation coefficients) are shown in thefigure. Significant positive correlations between insolublepSer129 α-syn and soluble Aβ42/Aβ40 were found in theparahippocampal (PH) cortex and thalamus (TH). Significantpositive correlations were also found between insolublepSer129 α-syn and insoluble Aβ42 in the cingulate (CG) and PHcortex. In addition, significant correlations were foundbetween insoluble pSer129 α-syn and insoluble Aβ40 in themidfrontal and CG cortex. Aβ, amyloid-β; pSer129 α-syn,alpha-synuclein phosphorylated at serine 129.
Mentions: In most regions the level of insoluble pSer129 α-synincreased as the levels of Aβ40 and Aβ42 increased (Figure 1, Additional file 3: Table S1), with significant positivecorrelations between insoluble pSer129 α-syn and soluble Aβ40 and Aβ42 inthe parahippocampal cortex (soluble Aβ40: r = 0.376, P = 0.003; soluble Aβ42: r = 0.287, P = 0.024) and thalamus (soluble Aβ40: r =0.398, P = 0.002; soluble Aβ42: r =0.404, P = 0.002). Significantpositive correlations were also found between insoluble pSer129 α-syn andinsoluble Aβ42 in the cingulate (r = 0.293, P = 0.022) and parahippocampal cortex (r = 0.314,P = 0.013) as well as betweeninsoluble pSer129 α-syn and insoluble Aβ40 in the midfrontal (r = 0.719,P <0.0001) and cingulate cortex(r = 0.304, P = 0.017). Significantnegative correlations between soluble pSer129 α-syn and soluble Aβ42 werefound in the cingulate cortex and thalamus (Figure 2; Additional file 3: Table S1) (cingulate cortex:r = −0.287, P = 0.035; thalamus:r = −0.373, P = 0.0036). In contrast,a significant positive correlation was observed between soluble Aβ42 andsoluble pSer129 α-syn in the midfrontal cortex (r = 0.443, P = 0.0015). Significant negativecorrelations between soluble Aβ40 and soluble pSer129 α-syn were found inthree of four regions (cingulate cortex: r = −0.313, P = 0.021; parahippocampal cortex:r = −0.286, P = 0.028; and thalamus: r = −0.376, P = 0.0033). Significant negative correlations were alsofound between soluble pSer129 α-syn and insoluble Aβ42 in the midfrontalcortex and thalamus (midfrontal cortex: r = −0.475, P = 0.0005; thalamus: r = −0.399, P = 0.0018). A significant positivecorrelation between soluble pSer129 α-syn and insoluble Aβ40 was alsofound in the parahippocampus (r = 0.316, P = 0.015).Figure 1

Bottom Line: In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains.In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn.Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).

View Article: PubMed Central - PubMed

Affiliation: Dementia Research Group, Institute of Clinical Neurosciences, School of Clinical Sciences, University of Bristol, Bristol, UK.

ABSTRACT

Introduction: Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn.

Methods: We measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson's disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage.

Results: In most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).

Conclusions: Together, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases.

No MeSH data available.


Related in: MedlinePlus