| 1. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Age and diagnostic performance of Alzheimer disease CSF biomarkers.
- 2012
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Ingår i: Neurology. - : American Academy of Neurology (AAN). - 1526-632X .- 0028-3878. ; 78:7, s. 468-76
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Tidskriftsartikel (refereegranskat)abstract
- Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.
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| 2. |
- Agholme, Lotta, et al.
(författare)
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Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition : Involvement of Autophagy
- 2012
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Ingår i: Journal of Alzheimer's Disease. - : I O S Press. - 1387-2877 .- 1875-8908. ; 31:2, s. 343-358
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Tidskriftsartikel (refereegranskat)abstract
- The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.
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| 3. |
- Agholme, Lotta, et al.
(författare)
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An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons
- 2010
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Ingår i: Journal of Alzheimer's Disease. - : Ios Press. - 1387-2877 .- 1875-8908. ; 20:4, s. 1069-1082
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Tidskriftsartikel (refereegranskat)abstract
- Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.
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| 4. |
- Agholme, Lotta
(författare)
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The involvement of degradation pathways and neuron-to-neuron transmission in Alzheimer’s disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although the vast majority of Alzheimer’s disease (AD) cases are of the sporadic type, mutations causing the familial form have been the focus of AD research for decades. The disease is pathologically characterised by β-amyloid (Aβ) and tau protein aggregates in neuritic plaques and neurofibrillary tangles. Furthermore, it is known that AD pathology spreads throughout the brain, most often along the same anatomical pattern. However, so far no cause for the sporadic form of the disease has been found. Accumulation of protein aggregates as well as decreased activity of the protein degradation systems, lysosomes and proteasomes, is found in diseased brains. This indicates that defective degradation contributes to sporadic AD.The aim of this thesis was to develop an improved neuronal model, and study the effects of decreased proteasome function on tau phosphorylation and axonal transport. In addition, the effects on Aβ accumulation and generation upon proteasome inhibition were investigated. Finally, the possibility that intracellularly accumulated Aβ oligomers could be transferred from one neuron to another was tested.Differentiation of human SH-SY5Y neuroblastoma cells in an extracellular matrix gel, using a set of neurotrophic factors, resulted in cells with neuronal phenotype, expressing neuron specific markers and all six adult isoforms of tau. Within this neuronal model, we found that reduced proteasome activity inhibited neuritic transport, and caused tau phosphorylation in a c-Jun and ERK 1/2 dependent manner. Using proteasome inhibition in APP overexpressing cells, we found an autophagy dependent intralysosomal Aβ accumulation, together with elevation of intra- and extracellular concentrations of Aβ. Autophagy inhibition protected the cells from the toxicity induced by decreased proteasome activity. Finally, we could, as the first group, show that Aβ can be directly transferred from one neuron to another through connected neurites. Furthermore, accumulation of Aβ in the endo-lysosomal compartment of receiving cells caused toxicity and neurodegeneration.We believe that cells not able to degrade accumulated Aβ, due to increased generation or reduced degradative capacity, instead tries to clear its content through transfer to connected neurons. If not properly degraded in the receiving cell, this can accelerate AD pathology and cause neuritic and neuronal degeneration spreading throughout the brain. Increasing the activity of the degradative systems, or inhibiting transmission of Aβ between neurons could therefore be novel treatments for AD.
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| 5. |
- Bagheri, Maryam
(författare)
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Neuroprotective Effect of Genistein : Studies in Rat Models of Parkinson’s and Alzheimer’s Disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that mainly affect the elderly population. It is believed that oxidative stress is involved in development of both these diseases and that estrogen deficiency is a risk factor for development of AD. Genistein is a plant-derived compound that is similar in structure to estrogen and has anti-oxidative properties. The general objective of the present research was to evaluate the effects of genistein on neurodegeneration in rat models of PD and AD.Using a rat model of PD, we found that a single intraperitoneal dose of genistein 1 h before intrastriatal injection of 6-hydroxydopamine (6-OHDA) attenuated apomorphine-induced rotational behavior and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity.To produce an animal model of AD, we injected Aβ1–40 into the hippocampus of rats. Using groups of these Aβ1–40-lesioned animals, the involvement of estrogen receptors (ERs) was evaluated by intracerebroventricular injection of the estrogen receptor antagonist fulvestrant, and the role of oxidative stress was studied by measuring levels of malondialdehyde (MDA), nitrite, and superoxide dismutase (SOD) activity. The results showed that intrahippocampal injection of Aβ1–40 caused the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in a radial arm maze (RAM task), elevated levels of MDA and nitrite, and a signiHcant reduction in SOD activity in the brain tissue. Furthermore, hippocampus in theses rats exhibited Aβ1–40 immunoreactive aggregates close to the lateral blade of the dentate gyrus (DGlb), extensive neuronal degeneration in the DGlb, high intracellular iNOS+ and nNOS+ immunoreactivity, and extensive astrogliosis.Genistein pretreatment ameliorated the Aβ-induced impairment of short-term spatial memory, and this effect occurred via an estrogenic pathway and through attenuation of oxidative stress. Genistein also ameliorated the degeneration of neurons, inhibited the formation of Aβ1–40-positive aggregates, and alleviated Aβ1–40-induced astrogliosis in the hippocampus.
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| 6. |
- Bjartmar, Lisa, 1966-, et al.
(författare)
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Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula
- 2010
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Ingår i: Brain Research. - : Elsevier. - 0006-8993 .- 1872-6240. ; 1328, s. 24-33
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, is involved in activity-dependent synaptogenesis and synaptic plasticity. In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. This study demonstrates that NP2 mRNA is robustly expressed in the hippocampus and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is enhanced in the hippocampal subregions as well as in the MHb after long-term treatment with antidepressant drugs of various monoaminergic profiles, indicating a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant induced plasticity, but not EE induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.
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| 7. |
- Degerman Gunnarsson, Malin, 1969-
(författare)
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Biomarkers as Monitors of Drug Effect, Diagnostic Tools and Predictors of Deterioration Rate in Alzheimer’s Disease
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Decreased amyloid-ß42 (Aß42), increased total tau (t-tau) and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) reflect histopathological core changes in the most common dementia disorder, Alzheimer’s disease (AD). They discriminate AD from healthy controls and predict conversion to AD with a relatively high accuracy. Memantine, an uncompetitive NMDA-receptor antagonist, is indicated for symptomatic treatment of AD. The first aim of this thesis was to investigate effects of memantine on CSF concentrations of Aβ42, tau and p-tau. Secondly, the aim was to explore the relation between these CSF biomarkers and retention of the amyloid biomarker Pittsburgh compound B using positron emission tomography (PIB PET), regional glucose metabolism measured with 18Fluoro-2-deoxy-d-glucose (FDG) PET and neuropsychological test performance. The third aim was to investigate their possible utility as predictors of future rate of AD dementia deterioration. All patients in the studies were recruited from the Memory Clinic, Uppsala University Hospital. In study I CSF p-tau concentrations in 11 AD patients were reduced after twelve months treatment with memantine, indicating that this compound may affect a key pathological process in AD. Results from study II showed that the concentrations of CSF Aß42 are lower in PIB+ patients than in PIB- patients, and that the PIB retention was stable during 12 months. In study III 10 patients with the diagnoses AD (6 PIB+/4 PIB-) and 8 subjects (1 PIB+/7 PIB-) with frontotemporal dementia were included. PIB+ patients had lower psychomotor speed measured by performance on the Trail Making Test A and impaired visual episodic memory compared to the PIB- patients. The initial clinical diagnoses were changed in 33% of the patients (6/18) during follow-up. Study IV is the first-ever report of an association between high CSF tau and dying in severe dementia. These 196 AD patients were followed up to nine years after baseline lumbar puncture. Moreover, CSF t-tau concentrations above median was associated with an increased risk of rapid cognitive decline (OR 3.31 (95% CI 1.53-7.16), independently of baseline functional stage. Thus, a clear association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease was shown.
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| 8. |
- Dong, Huan-Ji, et al.
(författare)
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Health Consequences Associated with Being Overweight or Obese: A Swedish Population-Based Study of 85-Year-Olds
- 2012
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Ingår i: Journal of The American Geriatrics Society. - : Wiley-Blackwell. - 0002-8614 .- 1532-5415. ; 60:2, s. 243-250
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To determine whether being overweight or obese is associated with significant health outcomes in an 85-year-old population. less thanbrgreater than less thanbrgreater thanDESIGN: A cross-sectional population-based study. less thanbrgreater than less thanbrgreater thanSETTING: Linkoping, Sweden. less thanbrgreater than less thanbrgreater thanPARTICIPANTS: Three hundred thirty-eight people born in 1922 were identified using the local authoritys register. less thanbrgreater than less thanbrgreater thanMEASUREMENTS: Data related to sociodemographic characteristics, health-related quality of life (HRQoL), assistance use, and the presence of diseases were collected using a postal questionnaire. Anthropometry and functional status were assessed during home and geriatric clinic visits. Diseases were double-checked in the electronic medical records, and information about health service consumption was obtained from the local healthcare register. less thanbrgreater than less thanbrgreater thanRESULTS: Overweight (body mass index (BMI) 25.0-29.9 kg/m(2)) and obese (BMI andgt;= 30.0 kg/m(2)) participants perceived more difficulty performing instrumental activities of daily living (IADLs) and had more comorbidity than their normal-weight counterparts (BMI 18.5-24.9 kg/m(2)), but their overall HRQoL and health service costs did not differ from those of normal-weight participants. After controlling for sociodemographic factors, being overweight did not influence IADLs or any comorbidity, but obese participants were more likely to perceive greater difficulty in performing outdoor activities (odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.1-4) and cleaning (OR = 2.2, 95% CI = 1.2-4.2) than their normal-weight counterparts. Although obesity was also associated with multimorbidity (OR = 3, 95% CI = 1.2-8), the health service cost of each case of multimorbidity (n = 251) was highest in normalweight participants and nearly three times as much as in obese participants (ratio: 2.9, 95% CI = 1.1-8.1). less thanbrgreater than less thanbrgreater thanCONCLUSION: For 85-year-olds, being obese, as opposed to overweight, is associated with self-reported activity limitations and comorbidities. Overweight older adults living in their own homes in this population had well-being similar to that of those with normal weight.
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| 9. |
- Dong, Huan-Ji, et al.
(författare)
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Multimorbidity patterns of and use of health services by Swedish 85-year-olds: an exploratory study
- 2013
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Ingår i: BMC Geriatrics. - : BioMed Central. - 1471-2318. ; 13:120
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAs life expectancy continues to rise, more elderly are reaching advanced ages (≥80 years). The increasing prevalence of multimorbidity places additional demands on health-care resources for the elderly. Previous studies noted the impact of multimorbidity on the use of health services, but the effects of multimorbidity patterns on health-service use have not been well studied, especially for very old people. This study determines patterns of multimorbidity associated with emergency-room visits and hospitalization in an 85-year-old population.MethodsHealth and living conditions were reported via postal questionnaire by 496 Linköping residents aged 85 years (189 men and 307 women). Diagnoses of morbidity were reviewed in patients’ case reports, and the local health-care register provided information on the use of health services. Hierarchical cluster analysis was applied to evaluate patterns of multimorbidity with gender stratification. Factors associated with emergency-room visits and hospitalization were analyzed using logistic regression models.ResultsCluster analyses revealed five clusters: vascular, cardiopulmonary, cardiac (only for men), somatic–mental (only for men), mental disease (only for women), and three other clusters related to aging (one for men and two for women). Heart failure in men (OR = 2.4, 95% CI = 1–5.7) and women (OR = 3, 95% CI = 1.3–6.9) as a single morbidity explained more variance than morbidity clusters in models of emergency-room visits. Men's cardiac cluster (OR = 1.6; 95% CI = 1–2.7) and women's cardiopulmonary cluster (OR = 1.7, 95% CI = 1.2–2.4) were significantly associated with hospitalization. The combination of the cardiopulmonary cluster with the men’s cardiac cluster (OR = 1.6, 95% CI = 1–2.4) and one of the women’s aging clusters (OR = 0.5, 95% CI = 0.3–0.8) showed interaction effects on hospitalization.ConclusionIn this 85-year-old population, patterns of cardiac and pulmonary conditions were better than a single morbidity in explaining hospitalization. Heart failure was superior to multimorbidity patterns in explaining emergency-room visits. A holistic approach to examining the patterns of multimorbidity and their relationships with the use of health services will contribute to both local health care policy and geriatric practice.
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| 10. |
- Hallbeck, Martin, et al.
(författare)
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Neuron-to-Neuron Transmission of Neurodegenerative Pathology
- 2013
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Ingår i: The Neuroscientist. - : Sage Publications. - 1073-8584 .- 1089-4098. ; 19:6, s. 560-566
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Forskningsöversikt (refereegranskat)abstract
- One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of -amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases.
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