| 1. |
- Gao, Yang, et al.
(författare)
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Live Cell FRET Imaging Reveals Amyloid beta-Peptide Oligomerization in Hippocampal Neurons
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:9
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta-peptide (A beta) oligomerization is believed to contribute to the neuronal dysfunction in Alzheimer disease (AD). Despite decades of research, many details of A beta oligomerization in neurons still need to be revealed. Forster resonance energy transfer (FRET) is a simple but effective way to study molecular interactions. Here, we used a confocal microscope with a sensitive Airyscan detector for FRET detection. By live cell FRET imaging, we detected A beta 42 oligomerization in primary neurons. The neurons were incubated with fluorescently labeled A beta 42 in the cell culture medium for 24 h. A beta 42 were internalized and oligomerized in the lysosomes/late endosomes in a concentration-dependent manner. Both the cellular uptake and intracellular oligomerization of A beta 42 were significantly higher than for A beta 40. These findings provide a better understanding of A beta 42 oligomerization in neurons.
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| 2. |
- Schedin-Weiss, Sophia, et al.
(författare)
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Super-resolution microscopy reveals gamma-secretase at both sides of the neuronal synapse
- 2016
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Ingår i: Acta neuropathologica communications. - : BioMed Central. - 2051-5960. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The transmembrane protein assembly gamma-secretase is a key protease in regulated intramembrane processing (RIP) of around 100 type-1 transmembrane proteins. Importantly, it has a pathological role in Alzheimer disease (AD) as it generates the neurotoxic amyloid beta-peptide from the amyloid precursor protein (APP). Studies on gamma-secretase location are therefore crucial both from a biological and a therapeutic perspective. Despite several years of efforts in many laboratories, it is not clear where in the neuron gamma-secretase exerts it's activities. Technical challenges include the fact that the active enzyme contains four protein components and that most subcellular compartments cannot be spatially resolved by traditional light microscopy. Here, we have used a powerful combination of the two nanoscopy techniques STORM and STED microscopy to visualize the location of gamma-secretase in neurons using an active-site specific probe, with a focus on the synapse. We show that gamma-secretase is present in both the pre-and postsynaptic compartments. We further show that the enzyme is enriched very close to the synaptic cleft in the postsynaptic membrane, as well as to NMDA receptors, demonstrating that gamma-secretase is present in the postsynaptic plasma membrane. Importantly, the expression of gamma-secretase increased in the pre-and postsynaptic compartments with the size of the synapse, suggesting a correlation between gamma-secretase activity and synapse maturation. Thus, our data shows the synaptic location with high precision in three dimensions and settles the long-lasting debate on the synaptic location of gamma-secretase.
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| 3. |
- Sillén, Anna, et al.
(författare)
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Expanded high-resolution genetic study of 109 Swedish families with Alzheimer's disease
- 2008
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 16:2, s. 202-208
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disease that affects approximately 20 million persons all over the world. There are both sporadic and familial forms of AD. We have previously reported a genome-wide linkage analysis on 71 Swedish AD families using 365 genotyped microsatellite markers. In this study, we increased the number of individuals included in the original 71 analysed families besides adding 38 new families. These 109 families were genotyped for 1100 novel microsatellite markers. The present study reports on the linkage data generated from the non-overlapping genotypes from the first genome scan and the genotypes of the present scan, which results in a total of 1289 successfully genotyped markers at an average density of 2.85 cM on 468 individuals from 109 AD families. Non-parametric linkage analysis yielded a significant multipoint LOD score in chromosome 19q13, the region harbouring the major susceptibility gene APOE, both for the whole set of families (LOD = 5.0) and the APOE epsilon 4-positive subgroup made up of 63 families (LOD = 5.3). Other suggestive linkage peaks that were observed in the original genome scan of 71 Swedish AD families were not detected in this extended analysis, and the previously reported linkage signals in chromosomes 9, 10 and 12 were not replicated.
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| 4. |
- Sillén, Anna, et al.
(författare)
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Linkage Analysis of Autopsy-Confirmed Familial Alzheimer Disease Supports an Alzheimer Disease Locus in 8q24
- 2011
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 31:2, s. 109-118
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: We have previously reported the results of an extended genome-wide scan of Swedish Alzheimer disease (AD)-affected families; in this paper, we analyzed a subset of these families with autopsy-confirmed AD. Methods: We report the fine-mapping, using both microsatellite markers and single-nucleotide polymorphisms (SNPs), in the observed maximum logarithm of the odds (LOD)-2 unit (LODmax-2) region under the identified linkage peak, linkage analysis of the fine-mapping data with additionally analyzed pedigrees, and association analysis of SNPs selected from candidate genes in the linked interval. The subset was made on the criterion of at least one autopsy-confirmed AD case per family, resulting in 24 families. Results: Linkage analysis of a family subset having at least one autopsy-confirmed AD case showed a significant nonparametric single-point LOD score of 4.4 in 8q24. Fine-mapping under the linkage peak with 10 microsatellite markers yielded an increase in the multipoint (mpt) LOD score from 2.1 to 3.0. SNP genotyping was performed on 21 selected candidate transcripts of the LODmax-2 region. Both family-based association and linkage analysis were performed on extended material from 30 families, resulting in a suggestive linkage at peak marker rs6577853 (mpt LOD score = 2.4). Conclusion: The 8q24 region has been implicated to be involved in AD etiology.
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| 5. |
- Sillén, Anna, et al.
(författare)
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Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia
- 2010
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 55:10, s. 649-655
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed at identifying novel susceptibility genes for a mixed phenotype of Alzheimer's disease and vascular dementia. Results from a genome scan showed strongest linkage to 20p13 in 18 families, and subsequent fine mapping was performed with both microsatellites and single-nucleotide polymorphisms in 18 selected candidate transcripts in an extended sample set of 30 families. The multipoint linkage peak was located at marker rs2144151 in the ANGPT4 gene, which is a strong candidate gene for vascular disease because of its involvement in angiogenesis. Although the significance of the linkage decreased, we find this result intriguing, considering that we included additional families, and thus the reduced linkage signal may be caused by genetic heterogeneity.
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| 6. |
- Yu, Yang, et al.
(författare)
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Neuronal A beta 42 is enriched in small vesicles at the presynaptic side of synapses
- 2018
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Ingår i: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 1:3
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Tidskriftsartikel (refereegranskat)abstract
- The amyloid beta-peptide (A beta) is a physiological ubiquitously expressed peptide suggested to be involved in synaptic function, long-term potentiation, and memory function. The 42 amino acid-long variant (A beta 42) forms neurotoxic oligomers and amyloid plaques and plays a key role in the loss of synapses and other pathogenic events of Alzheimer disease. Still, the exact localization of A beta 42 in neurons and at synapses has not been reported. Here, we used super-resolution microscopy and show that A beta 42 was present in small vesicles in presynaptic compartments, but not in postsynaptic compartments, in the neurites of hippocampal neurons. Some of these vesicles appeared to lack synaptophysin, indicating that they differ from the synaptic vesicles responsible for neurotransmitter release. The A beta 42-containing vesicles existed in presynapses connected to stubby spines and mushroom spines, and were also present in immature presynapses. These vesicleswere scarce inother parts of the neurites, where A beta 42 was instead present in large, around 200-600 nm, vesicular structures. Three-dimensional super-resolution microscopy confirmed that A beta 42 was present in the presynapse and absent in the postsynapse.
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| 7. |
- Zhou, Robin Ziyue, et al.
(författare)
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A glycan epitope correlates with tau in serum and predicts progression to Alzheimer's disease in combination with APOE4 allele status
- 2023
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:7, s. 3244-3249
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: There is an urgent need for novel blood biomarkers for the detection of Alzheimer's disease (AD). We previously showed that levels of the bisecting N-acetylglucosamine glycan epitope was elevated in cerebrospinal fluid in AD. However, its diagnostic value in blood is unknown.METHODS: We analyzed blood levels of bisecting N-acetylglucosamine and total tau in a retrospective cohort of 233 individuals. Progression to AD was compared between the groups using Cox regression. The predictive value of the biomarkers was determined by logistic regression.RESULTS: Bisecting N-acetylglucosamine correlated with tau levels (p < 0.0001). Individuals with an intermediate tau/bisecting N-acetylglucosamine ratio had elevated AD risk (hazard ratio = 2.06, 95% confidence interval [CI]: 1.18–3.6). Moreover, a combined model including tau/bisecting N-acetylglucosamine ratio, apolipoprotein E (APOE) ε4 status, and Mini-Mental State Examination score predicted future AD (area under the curve = 0.81, 95% CI: 0.68–0.93).DISCUSSION: Bisecting N-acetylglucosamine in combination with tau is a valuable blood biomarker for predicting AD.
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