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- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease
- 2014
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Synaptic degeneration is an early pathogenic event in Alzheimer's disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples. Results: We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer's disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer's disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer's disease from controls with area under the curve of 0.901 (P < 0.0001). Conclusions: We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.
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| 2. |
- Guzman, Erika Avendano, et al.
(författare)
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Abundance of A beta(5-x) x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease
- 2014
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9, s. 13-
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Tidskriftsartikel (refereegranskat)abstract
- Background: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptide (A beta) within neurons. Additionally to full-length peptides, a great diversity of N-truncated A beta variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that A beta(x-42) isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and A beta(x-42) species have been pointed as crucial players in AD etiology, the A beta(5-x) isoforms have not received much attention. Results: The present study is the first to show immunohistochemical evidence of A beta(5-x) in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe A beta(5-x) peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of A beta(5-x) distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular A beta deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal A beta(5-x). Conclusions: Different degrees of A beta(5-x) accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular A beta(5-x), these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher A beta(5-x)-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving A beta(5-x) peptides and operating in a divergent way in the late and early onset forms of the disease.
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| 3. |
- Kempf, Stefan J., et al.
(författare)
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The cognitive defects of neonatally irradiated miceare accompanied by changed synaptic plasticity,adult neurogenesis and neuroinflammation
- 2014
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9, s. 57-
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Tidskriftsartikel (refereegranskat)abstract
- Background/purpose of the study: Epidemiological evidence suggests that low doses of ionising radiation(≤1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanismsunderlying such alterations are unknown. We investigated the long-term effects of low doses of total body gammaradiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration.Results: Significant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6–7months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synapticactin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synapticproteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synapticplasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. Thesechanges were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134).Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFαindicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistentlynegatively affected after irradiation, particularly at 1.0 Gy.Conclusion: These data suggest that neurocognitive disorders may be induced in adults when exposed at a youngage to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards andregulatory practices.
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