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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

Distinct Aβ isoform patterns in FAD and SAD. The figure shows OPLS-DA on the two classes SAD and FAD using the data shown in figure 2. (A) Score plot for FAD (open diamonds) and SAD (open circles). (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 5: Distinct Aβ isoform patterns in FAD and SAD. The figure shows OPLS-DA on the two classes SAD and FAD using the data shown in figure 2. (A) Score plot for FAD (open diamonds) and SAD (open circles). (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: The reason for the distinct subgrouping of SAD patients and FAD mutation carriers in Figure 3A was analyzed in detail by comparing their CSF Aβ isoform patterns specifically (Figure 5A). Both disease groups were characterized by similar levels of Aβ1-42 and Aβ1-40, implying similar degrees of amyloid pathology in their brains [4,5]. However, FAD mutation carriers had very low concentrations of Aβ1-37, Aβ1-38 and Aβ1-39 and high Aβ1-20 compared with SAD patients (Figure 2). These deviations separated the two groups completely (Figure 5B and 5C). Similar Aβ1-37, Aβ1-38 and Aβ1-39 changes have been seen in media from cell lines expressing the PSEN1 Δ9 or L166P mutation, or the PSEN2 N141I mutation [11]. The Aβ1-37, Aβ1-38 and Aβ1-39 isoforms are normally produced by γ-secretase, suggesting that certain PSEN1 and PSEN2 mutations may modulate γ-secretase function by inhibiting cleavage at Gly37, Gly38 and Val39, without affecting the production of Aβ1-42 and Aβ1-40 significantly. It is tempting to speculate that Aβ1-37, Aβ1-38 and Aβ1-39 may inhibit Aβ1-42 oligomerization by forming less aggregation-prone heterocomplexes with Aβ1-42. Such a protective effect has recently been described for Aβ1-40 [23,24]. The key AD-promoting effect of PSEN1 A431E, and possibly several other FAD-associated PSEN mutations, may thus be a tweaked γ-secretase cleavage site preference that results in loss of C-terminally truncated Aβ species. Modulating γ-secretase function to boost cleavages at Gly37, Gly38 and Val39 would in that case be a novel approach to prevent AD-associated Aβ aggregation. However, prior to such a claim, the hypothesis that Aβ1-37, Aβ1-38 and Aβ1-39 indeed inhibit Aβ1-42 oligomerization and toxicity must be tested in additional studies.


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)

Distinct Aβ isoform patterns in FAD and SAD. The figure shows OPLS-DA on the two classes SAD and FAD using the data shown in figure 2. (A) Score plot for FAD (open diamonds) and SAD (open circles). (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 5: Distinct Aβ isoform patterns in FAD and SAD. The figure shows OPLS-DA on the two classes SAD and FAD using the data shown in figure 2. (A) Score plot for FAD (open diamonds) and SAD (open circles). (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: The reason for the distinct subgrouping of SAD patients and FAD mutation carriers in Figure 3A was analyzed in detail by comparing their CSF Aβ isoform patterns specifically (Figure 5A). Both disease groups were characterized by similar levels of Aβ1-42 and Aβ1-40, implying similar degrees of amyloid pathology in their brains [4,5]. However, FAD mutation carriers had very low concentrations of Aβ1-37, Aβ1-38 and Aβ1-39 and high Aβ1-20 compared with SAD patients (Figure 2). These deviations separated the two groups completely (Figure 5B and 5C). Similar Aβ1-37, Aβ1-38 and Aβ1-39 changes have been seen in media from cell lines expressing the PSEN1 Δ9 or L166P mutation, or the PSEN2 N141I mutation [11]. The Aβ1-37, Aβ1-38 and Aβ1-39 isoforms are normally produced by γ-secretase, suggesting that certain PSEN1 and PSEN2 mutations may modulate γ-secretase function by inhibiting cleavage at Gly37, Gly38 and Val39, without affecting the production of Aβ1-42 and Aβ1-40 significantly. It is tempting to speculate that Aβ1-37, Aβ1-38 and Aβ1-39 may inhibit Aβ1-42 oligomerization by forming less aggregation-prone heterocomplexes with Aβ1-42. Such a protective effect has recently been described for Aβ1-40 [23,24]. The key AD-promoting effect of PSEN1 A431E, and possibly several other FAD-associated PSEN mutations, may thus be a tweaked γ-secretase cleavage site preference that results in loss of C-terminally truncated Aβ species. Modulating γ-secretase function to boost cleavages at Gly37, Gly38 and Val39 would in that case be a novel approach to prevent AD-associated Aβ aggregation. However, prior to such a claim, the hypothesis that Aβ1-37, Aβ1-38 and Aβ1-39 indeed inhibit Aβ1-42 oligomerization and toxicity must be tested in additional studies.

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