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Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease.

Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, Hansson O, Harmsen A, Gustavsson MK, Hanse E, Galasko D, Hampel H, Blennow K, Zetterberg H - Mol Neurodegener (2010)

Bottom Line: SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information.PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

ABSTRACT

Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups.

Results: We measured Abeta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.

Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

No MeSH data available.


Related in: MedlinePlus

The Aβ isoform pattern separates SAD from controls and depressed patients. The figure shows OPLS-DA on the two classes SAD and non-AD (controls and depression) using the data shown in figure 2. (A) Score plot for SAD (open circles), depression (solid squares) and controls (solid triangles). (B) Loading and (C) variable importance on projection (VIP) plots for the Aβ fragments. The error bars in (C) represent a 95% confidence interval.
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Figure 4: The Aβ isoform pattern separates SAD from controls and depressed patients. The figure shows OPLS-DA on the two classes SAD and non-AD (controls and depression) using the data shown in figure 2. (A) Score plot for SAD (open circles), depression (solid squares) and controls (solid triangles). (B) Loading and (C) variable importance on projection (VIP) plots for the Aβ fragments. The error bars in (C) represent a 95% confidence interval.

Mentions: Representative CSF Aβ isoform mass spectra for SAD patients, FAD mutation carriers and controls are shown in Figure 1. Normalized CSF Aβ isoform intensities (Figure 2) were compared across the three groups using multivariate discriminant analysis (Figure 3). FAD patients were clearly separated from SAD and non-AD (controls and depression), and the latter two groups were also segregated from each other, although to a lesser extent. In order to ease the interpretation, subsequent pairwise discriminant analysis were performed for SAD patients vs. non-AD and SAD vs. FAD. Low levels of Aβ1-42 and high levels of Aβ1-16 were the main contributors for the separation of SAD from non-AD (Figure 4). Aβ1-34, Aβ1-17, Aβ1-13 and Aβ1-14 contributed weakly to the separation. Low CSF Aβ1-42 is a well-replicated finding in AD [21]. However, elevated Aβ1-16 in AD is less well known. The data presented herein, along with earlier results from independent data sets [16], show that SAD patients tend to express high levels of Aβ1-16 in their CSF at the group level, which also seems to hold true for PSEN1 A431E mutation carriers (Figure 2). Two SAD patients had very high Aβ1-16 levels (Figure 2). These patients, one male and one female, were 77 and 79 years old and did not differ from other SAD patients with regards to cognitive scores or Aβ1-42 concentrations. The reason for their very high Aβ1-16 levels is at present unknown.


Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease.

Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, Hansson O, Harmsen A, Gustavsson MK, Hanse E, Galasko D, Hampel H, Blennow K, Zetterberg H - Mol Neurodegener (2010)

The Aβ isoform pattern separates SAD from controls and depressed patients. The figure shows OPLS-DA on the two classes SAD and non-AD (controls and depression) using the data shown in figure 2. (A) Score plot for SAD (open circles), depression (solid squares) and controls (solid triangles). (B) Loading and (C) variable importance on projection (VIP) plots for the Aβ fragments. The error bars in (C) represent a 95% confidence interval.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2818651&req=5

Figure 4: The Aβ isoform pattern separates SAD from controls and depressed patients. The figure shows OPLS-DA on the two classes SAD and non-AD (controls and depression) using the data shown in figure 2. (A) Score plot for SAD (open circles), depression (solid squares) and controls (solid triangles). (B) Loading and (C) variable importance on projection (VIP) plots for the Aβ fragments. The error bars in (C) represent a 95% confidence interval.
Mentions: Representative CSF Aβ isoform mass spectra for SAD patients, FAD mutation carriers and controls are shown in Figure 1. Normalized CSF Aβ isoform intensities (Figure 2) were compared across the three groups using multivariate discriminant analysis (Figure 3). FAD patients were clearly separated from SAD and non-AD (controls and depression), and the latter two groups were also segregated from each other, although to a lesser extent. In order to ease the interpretation, subsequent pairwise discriminant analysis were performed for SAD patients vs. non-AD and SAD vs. FAD. Low levels of Aβ1-42 and high levels of Aβ1-16 were the main contributors for the separation of SAD from non-AD (Figure 4). Aβ1-34, Aβ1-17, Aβ1-13 and Aβ1-14 contributed weakly to the separation. Low CSF Aβ1-42 is a well-replicated finding in AD [21]. However, elevated Aβ1-16 in AD is less well known. The data presented herein, along with earlier results from independent data sets [16], show that SAD patients tend to express high levels of Aβ1-16 in their CSF at the group level, which also seems to hold true for PSEN1 A431E mutation carriers (Figure 2). Two SAD patients had very high Aβ1-16 levels (Figure 2). These patients, one male and one female, were 77 and 79 years old and did not differ from other SAD patients with regards to cognitive scores or Aβ1-42 concentrations. The reason for their very high Aβ1-16 levels is at present unknown.

Bottom Line: SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information.PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

ABSTRACT

Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (Abeta) in the brain, which is reflected by low concentration of the Abeta1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Abeta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Abeta. Here, we test the hypothesis that AD is characterized by a specific CSF Abeta isoform pattern that is distinct when comparing sporadic AD (SAD) and familial AD (FAD) due to different mechanisms underlying brain amyloid pathology in the two disease groups.

Results: We measured Abeta isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1) A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Abeta1-42 and high levels of Abeta1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Abeta1-42 and Abeta1-16, but FAD mutation carriers exhibited very low levels of Abeta1-37, Abeta1-38 and Abeta1-39.

Conclusion: SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Abeta isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Abeta1-37, Abeta1-38 and Abeta1-39; fragments that are normally produced by gamma-secretase, suggesting that the PSEN1 A431E mutation modulates gamma-secretase cleavage site preference in a disease-promoting manner.

No MeSH data available.


Related in: MedlinePlus