| 1. |
- Cedazo-Minguez, Ángel
(författare)
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Apolipoprotein E and Alzheimer's diseases : signals and effects
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer's Disease (AD) is the most frequent cause of dementia in the elderly. A diagnosis of AD is confirmed post-mortem by the accumulation of neuritic plaques (NP) and neurofibrillary tangles (NFTs) in brain tissue. NPs are extracellular deposits composed mainly of amyloid beta-peptide (A-beta) that is derived from the P amyloid precursor protein (APP). NFTs are found inside neurons and are characterised by structures referred to as paired helical filaments, whose major component is an abnormally phosphorylated and glycosylated form of the 'tau' protein. The most important risk factor for AD is polymorphism in the apolipoprotein E (apoE) gene. The apoE gene polymorphism gives rise to three different protein isoforms that differ in one single amino acid substitution and which show different lipid binding properties and three dimensional structure. The dose of the apoE4 isoform both increases the risk and reduces the age of onset for AD. The molecular mechanisms underlying this association are not fully understood, and in many cases are controversial. The present thesis, focuses on investigating several aspects of apoE biology in the context of AD. Paper I characterised factors that regulate apoE secretion in brain. ApoE secretion was shown to be modulated by adenosine 3':5'-cyclic monophosphate (cAMP) and factors that regulate intracellular cAMP. Retinoic acid potentiated, while the protein kinase C (PKC) activator phorbol 12- myristate 13-acetate (PMA) reversed the cAMP mediated effect. High PMA concentrations decreased apoE secretion. Also several agonists linked to the phospholipase C/PKC signalling pathway had opposite effects on apoE secretion, suggesting that the regulation of apoE by PKC may result from both positive and negative mechanisms. PKC activation and cAMP had opposite effects on nerve growth factor secretion than those seen for apoE secretion. Paper II aimed to clarify the interactions between A-beta, apoE isoforms and apoE containing lipoproteins with respect to neurotoxicity. In human SH-SY5Y neuroblastoma cells, both apoE3 and E4 were toxic when used alone but not when associated with P-very low density lipoproteins (beta-VLDL). Beta-VLDL also reduced the toxicity of A beta. These results suggest that the conformation of lipoprotein containing apoE particles may be important for determining the direct apoE contribution to neurotoxicity. No toxic effects were found in human fibroblasts, suggesting cell specificity. Papers III, IV and V explored the hypothesis that apoE may act as modulator of intracellular signalling pathways implicated in AD pathology. Paper III showed that apoE activates PKC without either isoform specific effects or further consequences for alpha-secretase APP cleavage. Paper IV showed that apoE4 and A-beta(1-42), but not apoE3, disrupt carbachol-induced phosphoinositide (P1) hydrolysis by an oxidative stress mediated mechanism. Moreover, apoE3 protected against the A-beta effect. Both apoE4 and A-beta(1-42) mediated disruptions of PI hydrolysis were protected by estrogen via an antioxidant effect and activation of phosphatidylinositol 3-kinase (PI3K). These findings may help to explain the lower effectiveness of treatments for AD based on cholinergic enhancers in apoE4 carriers, as well as shedding light on the protective mechanism of action of estrogen in AD. Paper V showed apoE isoform differences on the regulation of glycogen synthase kinase-3 beta (GSK-3 beta) activity. ApoE3 induced a mild transient early activation of GSK-3 beta that was possibly balanced by PKC activation. In contrast, apoE4 regulated GSK-30 activity in a biphasic manner, with a strong early activation and a subsequent inactivation of GSK-3 beta. ApoE4 also activated PKC-alpha and PKB, which may have given the subsequent GSK-3 beta inhibition. A beta(1-42) modulation of GSK-3 beta activity was also biphasic with a strong early activation and a subsequent inactivation. A beta(1-42) also induced an early and potent activation of PKC-alpha and a decreased PKB activity. These studies provide insight into some of the factors that control apoE secretion in brain and the neurotoxic effects of variant apoE isoforms. They also provide evidence that apoE has isoform specific effects on several signalling cascades involved in A beta production, tau phosphorylation, and apoptosis.
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| 2. |
- Daniilidou, Makrina, et al.
(författare)
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Alzheimer's disease biomarker profiling in a memory clinic cohort without common comorbidities.
- 2023
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Ingår i: Brain communications. - 2632-1297. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors to disease progression. However, less is known about their mechanistic contribution to Alzheimer's pathology and neurodegeneration. The aim of this study was to investigate the relationship of several biomarkers related to risk mechanisms in Alzheimer's disease with the well-established Alzheimer's disease markers in a memory clinic population without common comorbidities. We investigated 13 molecular markers representing key mechanisms underlying Alzheimer's disease pathogenesis in CSF from memory clinic patients without diagnosed hypertension, hypercholesterolaemia or diabetes nor other neurodegenerative disorders. An analysis of covariance was used to compare biomarker levels between clinical groups. Associations were analysed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were analysed by immunofluorescence staining in the hippocampus of non-demented control and Alzheimer's disease individuals. CSF samples from a total of 90 participants were included in this study: 30 from patients with subjective cognitive decline (age 62.4 ± 4.38, female 60%), 30 with mild cognitive impairment (age 65.6 ± 7.48, female 50%) and 30 with Alzheimer's disease (age 68.2 ± 7.86, female 50%). Angiotensinogen, thioredoxin-1 and interleukin-15 had the most prominent associations with Alzheimer's disease pathology, synaptic and axonal damage markers. Synaptosomal-associated protein 25kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer's disease patients. Grouping biomarkers by biological function showed that inflammatory and survival components were associated with Alzheimer's disease pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In the data-driven analysis, two patient clusters were identified: Cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared with Cluster 2. Clinical groups were evenly distributed between the clusters. An analysis of post-mortem hippocampal tissue showed that compared with non-demented controls, angiotensinogen staining was higher in Alzheimer's disease and co-localized with phosphorylated-tau. The identification of biomarker-driven endophenotypes in cognitive disorder patients further highlights the biological heterogeneity of Alzheimer's disease and the importance of tailored prevention and treatment strategies.
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| 3. |
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| 4. |
- Eroli, Francesca, et al.
(författare)
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Chronic polypharmacy impairs explorative behavior and reduces synaptic functions in young adult mice
- 2020
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 12:11, s. 10147-10161
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in the health care system is the lack of knowledge about the possible harmful effects of multiple drug treatments in old age. The present study aims to characterize a mouse model of polypharmacy, in order to investigate whether long-term exposure to multiple drugs could lead to adverse outcomes. To this purpose we selected five drugs from the ten most commonly used by older adults in Sweden (metoprolol, paracetamol, aspirin, simvastatin and citalopram). Five-month-old wild type male mice were fed for eight weeks with control or polypharmacy diet. We report for the first time that young adult polypharmacy-treated mice showed a significant decrease in exploration and spatial working memory compared to the control group. This memory impairment was further supported by a significant reduction of synaptic proteins in the hippocampus of treated mice. These novel results suggest that already at young adult age, use of polypharmacy affects explorative behavior and synaptic functions. This study underlines the importance of investigating the potentially negative outcomes from concomitant administration of different drugs, which have been poorly explored until now. The mouse model proposed here has translatable findings and can be applied as a useful tool for future studies on polypharmacy.
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| 5. |
- Francesca, Eroli, et al.
(författare)
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Long-term exposure to polypharmacy impairs cognitive functions in young adult female mice
- 2021
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 13:11, s. 14729-14744
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Tidskriftsartikel (refereegranskat)abstract
- The potential harmful effects of polypharmacy (concurrent use of 5 or more drugs) are difficult to investigate in an experimental design in humans. Moreover, there is a lack of knowledge on sex-specific differences on the outcomes of multiple-drug use. The present study aims to investigate the effects of an eight-week exposure to a regimen of five different medications (metoprolol, paracetamol, aspirin, simvastatin and citalopram) in young adult female mice. Polypharmacy-treated animals showed significant impairment in object recognition and fear associated contextual memory, together with a significant reduction of certain hippocampal proteins involved in pathways necessary for the consolidation of these types of memories, compared to animals with standard diet. The impairments in explorative behavior and spatial memory that we reported previously in young adult male mice administered the same polypharmacy regimen were not observed in females in the current study. Therefore, the same combination of medications induced different negative outcomes in young adult male and female mice, causing a significant deficit in non-spatial memory in female animals. Overall, this study strongly supports the importance of considering sex-specific differences in designing safer and targeted multiple-drug therapies.
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| 6. |
- Gil-Bea, Francisco J, et al.
(författare)
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Insulin levels are decreased in the cerebrospinal fluid of women with prodomal Alzheimer's disease
- 2010
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Ingår i: Journal of Alzheimer's Disease. - Amsterdam; Washington : IOS Press. - 1387-2877 .- 1875-8908. ; 22:2, s. 405-413
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1-42) levels and cognitive score. Furthermore, total-tau/(Aβ1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1-42 ratio for early AD diagnosis in women.
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| 7. |
- Hooshmand, Babak, et al.
(författare)
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Vitamin D in Relation to Cognitive Impairment, Cerebrospinal Fluid Biomarkers, and Brain Volumes
- 2014
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 69:9, s. 1132-1138
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Tidskriftsartikel (refereegranskat)abstract
- Background. Low vitamin D status is associated with poorer cognitive function in older adults, but little is known about the potential impact on cerebrospinal fluid (CSF) biomarkers and brain volumes. The objective of this study was to examine the relations between plasma 25-hydroxyvitamin D (25(OH)D) and cognitive impairment, CSF biomarkers of Alzheimer's disease (AD), and structural brain tissue volumes. Methods. A total of 75 patients (29 with subjective cognitive impairment, 28 with mild cognitive impairment, 18 with AD) referred to the Memory Clinic at Karolinska University Hospital, Huddinge, Sweden were recruited. Plasma 25(OH)D, CSF levels of amyloid beta (A beta(1-42)), total-tau, and phosphorylated tau, and brain tissue volumes have been measured. Results. After adjustment for several potential confounders, the odds ratios (95% confidence interval) for cognitive impairment were as follows: 0.969 (0.948-0.990) per increase of 1 nmol/L of 25(OH) D and 4.19 (1.30-13.52) for 24(OH) D values less than 50 nmol/L compared with values greater than or equal to 50 nmol/L. Adjusting for CSF A beta(1-42) attenuated the 25(OH) D-cognition link. In a multiple linear regression analysis, higher 25(OH)D levels were related to higher concentrations of CSF A beta(1-42) and greater brain volumes (eg, white matter, structures belonging to medial temporal lobe). The associations between 25(OH)D and tau variables were not significant. Conclusions. This study suggests that vitamin D may be associated with cognitive status, CSF A beta(1-42) levels, and brain tissue volumes.
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| 8. |
- Höglund, Kina, 1976, et al.
(författare)
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Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration : A translatable marker of synaptic degeneration
- 2020
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- Synapse impairment is thought to be an early event in Alzheimer's disease (AD); dysfunction and loss of synapses are linked to cognitive symptoms that precede neuronal loss and neurodegeneration. Neurogranin (Ng) is a somatodendritic protein that has been shown to be reduced in brain tissue but increased in the cerebrospinal fluid (CSF) of AD patients compared to age-matched controls. High levels of CSF Ng have been shown to reflect a more rapid AD progression. To gauge the translational value of Ng as a biomarker, we developed a new, highly sensitive, digital enzyme-linked immunosorbent assay (ELISA) on the Simoa platform to measure Ng in both mouse and human CSF. We investigated and confirmed that Ng levels are increased in the CSF of patients with AD compared to controls. In addition, we explored how Ng is altered in the brain and CSF of transgenic mice that display progressive neuronal loss and synaptic degeneration following the induction of p25 overexpression. In this model, we found that Ng levels increased in CSF when neurodegeneration was induced, peaking after 2 weeks, while they decreased in brain. Our data suggest that CSF Ng is a biomarker of synaptic degeneration with translational value.
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| 9. |
- Ibáñez, Clara, et al.
(författare)
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Toward a predictive model of Alzheimer's disease progression using capillary electrophoresis-mass spectrometry metabolomics
- 2012
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 84:20, s. 8532-8540
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is the most prevalent form of dementia with an estimated worldwide prevalence of over 30 million people, and its incidence is expected to increase dramatically with an increasing elderly population. Up until now, cerebrospinal fluid (CSF) has been the preferred sample to investigate central nervous system (CNS) disorders since its composition is directly related to metabolite production in the brain. In this work, a nontargeted metabolomic approach based on capillary electrophoresis–mass spectrometry (CE–MS) is developed to examine metabolic differences in CSF samples from subjects with different cognitive status related to AD progression. To do this, CSF samples from 85 subjects were obtained from patients with (i) subjective cognitive impairment (SCI, i.e. control group), (ii) mild cognitive impairment (MCI) which remained stable after a follow-up period of 2 years, (iii) MCI which progressed to AD within a 2-year time after the initial MCI diagnostic and, (iv) diagnosed AD. A prediction model for AD progression using multivariate statistical analysis based on CE–MS metabolomics of CSF samples was obtained using 73 CSF samples. Using our model, we were able to correctly classify 97–100% of the samples in the diagnostic groups. The prediction power was confirmed in a blind small test set of 12 CSF samples, reaching a 83% of diagnostic accuracy. The obtained predictive values were higher than those reported with classical CSF AD biomarkers (Aβ42 and tau) but need to be confirmed in larger samples cohorts. Choline, dimethylarginine, arginine, valine, proline, serine, histidine, creatine, carnitine, and suberylglycine were identified as possible disease progression biomarkers. Our results suggest that CE–MS metabolomics of CSF samples can be a useful tool to predict AD progression.
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| 10. |
- Kivipelto, Miia, et al.
(författare)
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Apolipoprotein E epsilon 4 magnifies lifestyle risks for dementia : a population-based study
- 2008
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Ingår i: Journal of Cellular and Molecular Medicine (Print). - : Wiley. - 1582-1838 .- 1582-4934. ; 12:6B, s. 2762-2771
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Tidskriftsartikel (refereegranskat)abstract
- The risk of dementia and Alzheimer's disease (AD) probably results from an interaction between genetic and environmental factors. The aim of this study was to investigate the effects and putative interactions between the apoE epsilon 4 allele and lifestyle related risk factors for dementia and AD. Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in 1972, 1977, 1982 or 1987. After an average follow-up of 21 years, 1449 individuals (72.5%) aged 65-79 years were re-examined in 1998. The apoE epsilon 4 allele was an independent risk factor for dementia/AD even after adjustments for sociodemographic, lifestyle and vascular factors (odds ratio [OR] = 2.83, 95% confidence interval [CI] epsilon 1.61-4.97). Physical inactivity, alcohol drinking and smoking increased the risk of dementia/AD particularly among the apoE epsilon 4 carriers. Furthermore, low-moderate intake of polyunsaturated, and moderate-high intake of saturated fats were associated with an increased risk of dementia/AD more pronouncedly among apoE epsilon 4 carriers. Composite effect of the lifestyle factors was particularly seen among the epsilon 4 carriers (OR = 11.42, 95% CI = 1.94-67.07 in the 4(th) quartile). Physical inactivity, dietary fat intake, alcohol drinking and smoking at midlife are associated with the risk of dementia and AD, especially among the apoE epsilon 4 carriers. The apoE epsilon 4 carriers may be more vulnerable to environmental factors, and thus, lifestyle interventions may greatly modify dementia risk particularly among the genetically susceptible individuals.
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