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Increased γ-secretase activity in idiopathic normal pressure hydrocephalus patients with β-amyloid pathology.

Laiterä T, Sarajärvi T, Haapasalo A, Puli L, Kauppinen T, Mäkinen P, Rauramaa T, Tanila H, Jääskeläinen JE, Alafuzoff I, Soininen H, Leinonen V, Hiltunen M - PLoS ONE (2014)

Bottom Line: In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology).Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology.Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland; Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.

ABSTRACT
The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated β- and γ-secretase activities in relation to amyloid-β (Aβ) pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable Aβ plaques, γ-secretase activity was significantly increased (∼ 1.6-fold) when compared to iNPH samples without Aβ plaques (p = 0.009). In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, β-secretase activity was unaltered in iNPH samples with or without Aβ plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not β-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aβ pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.

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β- and γ-secretase activities show positive correlation among the AD patients.(A, B) Pearson’s correlation between relative β- and γ-secretase activities measured in the brain samples iNPH (A) and AD (B) patients. Statistically significant positive correlation is observed in the AD sample cohort, but not in the iNPH cohort.
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pone-0093717-g004: β- and γ-secretase activities show positive correlation among the AD patients.(A, B) Pearson’s correlation between relative β- and γ-secretase activities measured in the brain samples iNPH (A) and AD (B) patients. Statistically significant positive correlation is observed in the AD sample cohort, but not in the iNPH cohort.

Mentions: Before assessing β- and γ-secretase activities in the iNPH and AD tissue samples, both activity assays were validated using β- and γ-secretase-specific inhibitors. Activity measurements of the inhibitor-treated biopsy and post-mortem lysates revealed significant decrease in the β- and γ-secretase activity (Figure S1). Consequently, relative γ-secretase activity was found to be significantly higher in the iNPH samples with Aβ−plaques (Aβ+and Aβ++ samples) as compared to the iNPH samples without detectable Aβ−plaques (p = 0.009; Figure 2A and 2B). Conversely, no significant differences in the relative γ-secretase activity were observed in the inferior temporal cortical samples of AD patients with respect to disease severity (divided according to the Braak staging into mild, moderate and severe groups [11]) (Figure 2C). Moreover, comparison between different severity groups and subjects without neurofibrillary pathology ( =  Braak 0 group) did not reveal significant changes in the relative γ-secretase activity. Soluble Aβ42 levels were in turn increased significantly in relation to disease severity, while the soluble Aβ42 levels were robustly lower in the Braak 0 group as compared to mild, moderate and severe groups (Figure 2D). On the contrary to the increased γ-secretase activity, β-secretase activity was not significantly altered in the iNPH samples between different Aβ groups (Figure 3A and 3B), while a significant difference was observed in relation to AD severity in the AD cohort (p = 0.0003 between mild and severe and p = 0.02 between mild and moderate; Figure 3C). Also, β-secretase activity was significantly increased in the severe group as compared to the Braak 0 group. Activity of β- or γ-secretase did not significantly correlate with the relative Aβ−staining values among the iNPH samples (r = −0.200, p = 0.47 and r = −0.101, p = 0.69, respectively). Also, β-secretase and γ-secretase activity did not significantly correlate in the iNPH sample set (r = 0.399, p = 0.06; Figure 4A), while a robust correlation between the activity of these two secretases was noticed in the AD sample set (r = 0.542, p = 0.0000001; Figure 4B). Activity of β- or γ-secretase did not significantly correlate with the post-mortem delay (r = −0.177, p = 0.10 and r = −0.101, p = 0.36, respectively) or with the age of death (r = 0.142, p = 0.20 and r = 0.096, p = 0.38, respectively) in the AD cohort. Moreover, activity of β- or γ-secretase did not significantly correlate with the age of iNPH patients at the biopsy (r = −0.183 and p = 0.59 and r = −0.110 and p = 0.40, respectively).


Increased γ-secretase activity in idiopathic normal pressure hydrocephalus patients with β-amyloid pathology.

Laiterä T, Sarajärvi T, Haapasalo A, Puli L, Kauppinen T, Mäkinen P, Rauramaa T, Tanila H, Jääskeläinen JE, Alafuzoff I, Soininen H, Leinonen V, Hiltunen M - PLoS ONE (2014)

β- and γ-secretase activities show positive correlation among the AD patients.(A, B) Pearson’s correlation between relative β- and γ-secretase activities measured in the brain samples iNPH (A) and AD (B) patients. Statistically significant positive correlation is observed in the AD sample cohort, but not in the iNPH cohort.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3974803&req=5

pone-0093717-g004: β- and γ-secretase activities show positive correlation among the AD patients.(A, B) Pearson’s correlation between relative β- and γ-secretase activities measured in the brain samples iNPH (A) and AD (B) patients. Statistically significant positive correlation is observed in the AD sample cohort, but not in the iNPH cohort.
Mentions: Before assessing β- and γ-secretase activities in the iNPH and AD tissue samples, both activity assays were validated using β- and γ-secretase-specific inhibitors. Activity measurements of the inhibitor-treated biopsy and post-mortem lysates revealed significant decrease in the β- and γ-secretase activity (Figure S1). Consequently, relative γ-secretase activity was found to be significantly higher in the iNPH samples with Aβ−plaques (Aβ+and Aβ++ samples) as compared to the iNPH samples without detectable Aβ−plaques (p = 0.009; Figure 2A and 2B). Conversely, no significant differences in the relative γ-secretase activity were observed in the inferior temporal cortical samples of AD patients with respect to disease severity (divided according to the Braak staging into mild, moderate and severe groups [11]) (Figure 2C). Moreover, comparison between different severity groups and subjects without neurofibrillary pathology ( =  Braak 0 group) did not reveal significant changes in the relative γ-secretase activity. Soluble Aβ42 levels were in turn increased significantly in relation to disease severity, while the soluble Aβ42 levels were robustly lower in the Braak 0 group as compared to mild, moderate and severe groups (Figure 2D). On the contrary to the increased γ-secretase activity, β-secretase activity was not significantly altered in the iNPH samples between different Aβ groups (Figure 3A and 3B), while a significant difference was observed in relation to AD severity in the AD cohort (p = 0.0003 between mild and severe and p = 0.02 between mild and moderate; Figure 3C). Also, β-secretase activity was significantly increased in the severe group as compared to the Braak 0 group. Activity of β- or γ-secretase did not significantly correlate with the relative Aβ−staining values among the iNPH samples (r = −0.200, p = 0.47 and r = −0.101, p = 0.69, respectively). Also, β-secretase and γ-secretase activity did not significantly correlate in the iNPH sample set (r = 0.399, p = 0.06; Figure 4A), while a robust correlation between the activity of these two secretases was noticed in the AD sample set (r = 0.542, p = 0.0000001; Figure 4B). Activity of β- or γ-secretase did not significantly correlate with the post-mortem delay (r = −0.177, p = 0.10 and r = −0.101, p = 0.36, respectively) or with the age of death (r = 0.142, p = 0.20 and r = 0.096, p = 0.38, respectively) in the AD cohort. Moreover, activity of β- or γ-secretase did not significantly correlate with the age of iNPH patients at the biopsy (r = −0.183 and p = 0.59 and r = −0.110 and p = 0.40, respectively).

Bottom Line: In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology).Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology.Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland; Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland.

ABSTRACT
The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated β- and γ-secretase activities in relation to amyloid-β (Aβ) pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable Aβ plaques, γ-secretase activity was significantly increased (∼ 1.6-fold) when compared to iNPH samples without Aβ plaques (p = 0.009). In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, β-secretase activity was unaltered in iNPH samples with or without Aβ plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not β-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aβ pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.

Show MeSH
Related in: MedlinePlus