| 1. |
- 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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| 2. |
- 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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| 3. |
- Aho, Leena, et al.
(författare)
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Immunohistochemical Visualization of Amyloid-β Protein Precursor and Amyloid-β in Extra- and Intracellular Compartments in the Human Brain
- 2010
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 20:4, s. 1015-1028
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (Abeta) peptide, a cleavage product of the amyloid-beta protein precursor (AbetaPP), has been reported to be detected in the intracellular compartment. Most studies reporting the presence of intracellular Abeta are based on the use of immunohistochemistry. In this study, the presence of AbetaPP and Abeta was assessed by applying immunohistochemistry in postmortem human brain tissue samples obtained from 10 neurologically intact subjects, the youngest being 2 years of age, one aged with mild cognitive impairment, 14 neurologically diseased, and in one brain biopsy sample obtained from a subject with normal pressure hydrocephalus. Intracellular immunoreactivity was detected in all ages independent of the disease state or existence of extracellular Abeta aggregates with all antibodies directed to AbetaPP, with three Abeta antibodies (4G8, 6E10, and 82E1), clones that are unable to distinguish Abeta from AbetaPP. These results suggest that it is AbetaPP rather than Abeta that is detected intracellularly when using the antibodies listed above. Furthermore, the staining results varied when different pretreatment strategies were applied. Interestingly intracellular Abeta was detected with antibodies directed to the C-terminus of Abeta (neoepitope) in subjects with Alzheimer's disease. The lack of intracellular immunoreactivity in unimpaired subjects, when using antibodies against neoepitopes, may be due to a lack or a low level of the protein that is thus undetectable at light microscopic level by immunohistochemistry method. The staining results and conclusions depended strongly on the chosen antibody and the pretreatment strategy and thus multiple antibodies must be used when assessing the intracellular accumulation of Abeta.
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| 4. |
- Alafuzoff, Irina
(författare)
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Alzheimer's disease-related lesions
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 33:Suppl 1, s. S173-S179
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Forskningsöversikt (refereegranskat)abstract
- The invitation to contribute to "Alzheimer's Disease: Advances for a New Century" gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that the degenerative process is initiated much earlier than we ever suspected.
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| 5. |
- Alikhani, Nyosha, et al.
(författare)
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Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria
- 2011
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 27:1, s. 75-87
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Tidskriftsartikel (refereegranskat)abstract
- Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.
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| 6. |
- Atti, Anna Rita, et al.
(författare)
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Cognitive Impairment after Age 60 : clinical and Social Correlates in the "Faenza Project"
- 2010
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 21:4, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- A total of 7,389 dementia-free elderly (60–102 years old) enrolled in the "Faenza Project" (Northern Italy) were clinically evaluated by nurses and physicians with the aim of detecting the independent and combined association of medical and social factors with cognitive status. Cognitive Impairment No Dementia (CIND) was defined for MMSE scores ⩽ 2 standard deviations than the age- and education-corrected mean score obtained by the non-demented persons of the Faenza cohort. Logistic Regression analysis was used to estimate Odds Ratios and 95% Confidence Intervals (OR, 95%CI) for CIND. The diagnostic procedure identified 402 (5.4%) CIND cases. Diabetes (OR, 95%CI=1.6, 1.2–2.2), stroke (OR, 95%CI=1.9, 1.4–2.6), and depressive symptoms (OR, 95%CI=1.9, 1.4–2.7) emerged as the most relevant medical comorbidities of CIND. Low education (OR, 95%CI=1.8, 1.1–2.9), low Socio Economic Status (SES) (OR, 95%CI=1.5, 1.1–2.1), and unmarried status (OR, 95%CI=1.7, 1.2–2.5) were associated with CIND. Medical and social factors were independently related to CIND occurrence. In comparison to subjects without any of the above mentioned conditions, subjects with one medical and one social factor had an OR, 95%CI for CIND equal to 6.0, 2.9–12.4. The strength of the association increased when more of those conditions occurred in combination, suggesting a synergistic effect. Despite some methodological limitations, data from this cross-sectional population-based Italian study show that low education, low SES, unmarried status together with diabetes, stroke, and depressive symptoms are related to cognitive impairment in the general population. The interaction of medical and social factors further increases the probability of CIND.
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| 7. |
- Bengtsson, Sara K., et al.
(författare)
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Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 31:1, s. 71-84
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Tidskriftsartikel (refereegranskat)abstract
- The endogenous neurosteroid allopregnanolone alters neuronal excitability via modulation of the GABA(A) receptor and causes decreased neurotransmission. In Alzheimer's disease (AD), neurotransmission seems to alter the levels of toxic intracellular amyloid-beta (A beta) oligomers, which are implicated in AD pathogenesis and cause cognitive decline. Inhibition of synaptic activity has been shown to increase levels of intracellular A beta. Allopregnanolone at endogenous stress levels inhibits synaptic activity and could have similar effects. By using a transgenic A beta PP(Swe)PSEN1(Delta E9) mouse model for AD, we observed that chronic allopregnanolone treatment for three months with stress levels of allopregnanolone impaired learning in the Morris water maze. The learning impairment was seen one month after the end of treatment. Chronic allopregnanolone treatment also led to increased levels of soluble A beta in the brain, which could be a sign of advanced pathogenesis. Since the learning and memory of wild-type mice was not affected by the treatment, we propose that chronic allopregnanolone treatment accelerates the pathogenesis of AD. However, further studies are required in order to determine the underlying mechanism.
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| 8. |
- Caracciolo, Barbara, et al.
(författare)
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Differential distribution of subjective and objective cognitive impairment in the population : a nation-wide twin-study
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 29:2, s. 393-403
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Tidskriftsartikel (refereegranskat)abstract
- We report the prevalence of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND), their socio-demographic profile, and the contribution of genetic background and shared familial environment to SCI and CIND. Subjects were 11,926 dementia-free twin individuals aged ≥65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. Overall prevalence rates of SCI and CIND were 39% (95% CI 38-39%) and 25% (95% CI 24-25%). In multivariate GEE models, both SCI and CIND were older compared with people without any cognitive impairment. CIND were also less educated, more likely to be unmarried and to have lower socioeconomic status (SES). SCI individuals differed from persons with CIND as they were older, more educated, more likely to be married, and to have higher SES. Co-twin control analysis, which corrects for common genetic and shared environmental background, confirmed the association of low education with CIND. Probandwise concordance for SCI and CIND was 63% and 52% in monozygotic twins, 63% and 50% in dizygotic same-sex twins, and 42% and 29% in dizygotic unlike-sex twins. Tetrachoric correlations showed no significant differences between monozygotic and dizygotic same-sex twins. We conclude that subjective and objective cognitive impairment are both highly prevalent among nondemented elderly yet have distinct sociodemographic profiles. Shared environmental influences rather than genetic background play a role in the occurrence of SCI and CIND.
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| 9. |
- Caracciolo, Barbara, et al.
(författare)
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Relationship of Subjective Cognitive Impairment and Cognitive Impairment No Dementia to Chronic Disease and Multimorbidity in a Nation-Wide Twin Study
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 36:2, s. 275-284
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the relation of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND) to common chronic diseases of the elderly and multimorbidity, and assessed the contribution of genetic background and shared familial environment to these associations. Subjects were 11,379 dementia-free twin individuals aged >= 65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. In unmatched, fully-adjusted regression models, mental, musculoskeletal, respiratory, and urological diseases were all significantly associated with increased odds ratios (ORs) of SCI and CIND. Circulatory and gastrointestinal diseases were related to SCI only, while endocrine diseases were associated with CIND. The adjusted ORs of multimorbidity were 2.1 [95% confidence intervals (95% CI): 1.8-2.3] for SCI and 1.5 for CIND (95% CI: 1.3-1.8). A dose-dependent relationship was observed between number of chronic diseases and ORs for SCI but not for CIND. In co-twin control analyses, the chronic diseases-SCI association was largely unchanged. On the other hand, the chronic diseases-CIND association was no longer statistically significant, except for cancer, where an increased OR was observed. In conclusion, chronic morbidity is associated with both SCI and CIND but disease profiles do not always overlap between the two cognitive syndromes. The association is stronger when diseases co-occur, especially for SCI. Genetic and early-life environmental factors may partially explain the association of CIND but not that of SCI with chronic diseases.
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| 10. |
- Choo, Il Han, et al.
(författare)
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Combination of f 18 fdg pet and cerebrospinal fluid biomarkers as a better predictor of the progression to alzheimer's disease in mild cognitive impairment patients
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 33:4, s. 929-939
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Tidskriftsartikel (refereegranskat)abstract
- The biomarker-based new diagnostic criteria have been proposed for Alzheimer's disease (AD) spectrum. However, any biomarker alone has not been known to have satisfactory AD predictability. We explored the best combination model with baseline demography, neuropsychology, F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid (CSF) biomarkers, and apolipoprotein E (APOE) genotype evaluation to predict progression to AD in mild cognitive impairment (MCI) patients. Alongitudinal clinical follow-up (mean, 44 months; range, 1.6-161.7 months) of MCI patients was done. Among 83 MCI patients, 26 progressed to AD (MCI-AD) and 51 did not deteriorate (MCI-Stable). We applied that univariate and multivariate logistic regression analyses, and multistep model selection for AD predictors including biomarkers. In univariate logistic analysis, we selected age, Rey Auditory Verbal Retention Test, parietal glucose metabolic rate, CSF total tau, and presence or not of at least one APOE epsilon 4 allele as predictors. Through multivariate stepwise logistic analysis and model selection, we found the combination of parietal glucose metabolic rate and total tau representing the best model for AD prediction. In conclusion, our findings highlight that the combination of regional glucose metabolic assessment by PET and CSF biomarkers evaluation can significantly improve AD predictive diagnostic accuracy of each respective method.
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