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- Andreasson, U., et al.
(författare)
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An enzyme activity as a potential biomarker for Alzheimer's disease.
- 2010
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:4, s. 497-498
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Konferensbidrag (refereegranskat)abstract
- Background: Six different N-terminal amyloid precursor protein (APP) fragments, with molecular weight ∼12 kDa, have previously been identified in human cerebrospinal fluid (CSF). In a pilot study, both the sum of their concentrations, measured by western blot, and the relative abundance pattern, measured by mass spectrometry, were different in Alzheimer's disease (AD) patients compared to healthy controls. To test if these differences were also reflected in protease activities that possibly give rise to the ∼12 kDa fragments an enzymatic assay was developed and the activity in CSF was investigated for its potential as a biomarker for AD. Methods: The substrate in the protease activity assay was a custom made fluorochrome/quencher labeled peptide that covers the cleavage sites in APP (APP118-APP127) corresponding to the C-termini of the six ∼12 kDa APP fragments. The activity was measured in CSF from 55 AD patients and 17 controls. Results: There was a significant increase in the protease activity in CSF from AD patients compared to the controls (p = 0.001). This is in line with previous results which indicate that the sum of the ∼12 kDa fragments are elevated in AD. Results from inhibition studies strongly suggests that the enzyme responsible for the cleavage of the substrate is an aspartic protease since a sub nM IC50 value was recorded for Pepstatin A while no inhibition was observed for the cysteine protease specific inhibitor E64 at concentrations up to100 nM. Conclusions: There exists an enzymatic activity in CSF capable of cleaving a peptide substrate that spans a portion, close to the N-terminal, of APP. In a pilot study the activity is increased in AD patients compared to controls suggesting that it can be used as a biomarker.
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- Duchesne, Annie, et al.
(författare)
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Hippocampal Integrity in Swedish Women with Bilateral Salpingo-oophorectomy prior to Natural Menopause
- 2017
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Ingår i: Alzheimer's Association International Conference. - Hoboken, NJ, United States : John Wiley & Sons. ; , s. 1084-1084
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Konferensbidrag (refereegranskat)abstract
- Background:Oophorectomy prior to natural menopause places women at increased risk of dementia and/or Alzheimer's disease (AD). Recent findings from our Toronto group reveal a negative association between oophorectomy prior to natural menopause and verbal memory in middle-aged women. We have also found a positive association between estrogen levels and verbal recall. Taken together, these findings support previous work suggesting that oophorectomy, leading to reduced levels of estrogens, is detrimental to verbal memory. Estrogen withdrawal has also been correlated with reduced hippocampal volume and reduced hippocampal resting functional connectivity (FC), both early AD biomarkers. Thus, we wondered whether hippocampal volume and resting functional connectivity would be reduced in women with oophorectomy prior to natural menopause.Methods:In order to determine this, we recruited healthy, Swedish women (30 and 55 years) with the breast cancer mutation gene (BRCA1/2) who had a bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Most women were between 1–7 years post-BSO and at least 6 months post-cancer treatment or had not had cancer. Using magnetic resonance imaging (3T scanner, Phillips) we measured functional resting state over 10 minutes and volume with a T1 structural scan. We collected urine in order to determine estrogen and progesterone levels.Results:We hypothesize that women with BSO will have structural and functional hippocampal changes compared to age matched controls. We predict that women with BSO will have smaller hippocampal volumes and reduced hippocampal FC. We further predict that lower levels of estrogens will correlate with these brain changes. Neuroimaging and endocrine analyses are ongoing.Conclusions:AD affects women in greater numbers and one possibility is that oophorectomy prior to natural menopause contributes to these numbers. Determining whether or not these women show the earliest biomarkers for AD will increase our understanding of estrogen withdrawal's effects on brain health as well as its importance for healthy brain aging. Importantly, results of this study will inform us on the early brain changes in a population at greater risk of AD.
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- Johansson, Per, et al.
(författare)
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Convergence of chromogranin and amyloid metabolism in the brain.
- 2010
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:4, s. 511-511
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Konferensbidrag (refereegranskat)abstract
- Background: Much is unknown regarding the regulation of amyloid precursor protein (APP) processing in the human central nervous system. It has been hypothesized that amyloidogenic APP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of APP-derived molecules in CSF with chromogranin (Cg) derived peptides, representing the regulated secretion. Methods: Patients with Alzheimer's disease (AD, N = 32), multiple sclerosis (MS, N = 50) and healthy controls (N = 70) were enrolled. CSF was analyzed for the amyloid peptides Aβ1-42, Aβx-42, Aβx-40, Aβx-38, α-cleaved soluble APP (α-sAPP), β-cleaved soluble APP (β-sAPP), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes APP into Aβ, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. Results: CSF Cg levels correlated to sAPP and Aβ peptides in AD, MS and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. Conclusions: These results suggest that a large part of APP in the human central nervous system is processed in the regulated secretory pathway of neurons.
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