| 11. |
- Jiang, Hong, et al.
(författare)
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Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease.
- 2011
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: We recently reported that expression levels of tumor necrosis factor (TNF) receptors, TNFR1 and TNFR2, are significantly changed in the brains and cerebrospinal fluid (CSF) with Alzheimer's disease (AD). Moreover, we also found that, in an Alzheimer's mouse model, genetic deletion of TNF receptor (TNFR1) reduces amyloid plaques and amyloid beta peptides (Aβ) production through β-secretase (BACE1) regulation. TNF-α converting enzyme (TACE/ADAM-17) does not only cleave pro- TNF-α but also TNF receptors, however, whether the TACE activity was changed in the CSF was not clear. In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared to age- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are an early event in the course of AD, we measured these molecules in the CSF from 47 subjects with mild cognitive impairment (MCI), which is considered as a preclinical stage of AD. Unexpectedly, we found significantly higher levels of TACE activity and soluble TNFRs in the MCI group than that in AD patients. These results suggest that TACE activity and soluble TNF receptors may be potential diagnostic candidate biomarkers in AD and MCI.
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| 12. |
- 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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| 13. |
- Rogers, Kathryn, et al.
(författare)
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Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice.
- 2012
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Background: A hallmark of Alzheimer’s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer’s disease. Results: Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM) and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. Conclusions: EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer’s disease.
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| 14. |
- Sun, Yanyan, et al.
(författare)
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Apoptosis-inducing factor downregulation increased neuronal progenitor, but not stem cell, survival in the neonatal hippocampus after cerebral hypoxiaischemia.
- 2012
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: A considerable proportion of all newly generated cells in the hippocampus will die before becoming fully differentiated, both under normal and pathological circumstances. The caspase-independent apoptosis-inducing factor (AIF) has not been investigated previously in this context. RESULTS: Postnatal day 8 (P8) harlequin (Hq) mutant mice, expressing lower levels of AIF, and wild type littermates were injected with BrdU once daily for two days to label newborn cells. On P10 mice were subjected to hypoxia-ischemia (HI) and their brains were analyzed 4 h, 24 h or 4 weeks later. Overall tissue loss was 63.5% lower in Hq mice 4 weeks after HI. Shortterm survival (4 h and 24 h) of labeled cells in the subgranular zone was neither affected by AIF downregulation, nor by HI. Long-term (4 weeks) survival of undifferentiated, BLBPpositive stem cells was reduced by half after HI, but this was not changed by AIF downregulation. Neurogenesis, however, as judged by BrdU/NeuN double labeling, was reduced by half after HI in wild type mice but preserved in Hq mice, indicating that primarily neural progenitors and neurons were protected. A wave of cell death started early after HI in the innermost layers of the granule cell layer (GCL) and moved outward, such that 24 h after HI dying cells could be detected in the entire GCL. CONCLUSIONS: These findings demonstrate that AIF downregulation provides not only long-term overall neuroprotection after HI, but also protects neural progenitor cells, thereby rescuing hippocampal neurogenesis.
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| 15. |
- Barbariga, Marco, et al.
(författare)
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Ceruloplasmin functional changes in Parkinson's disease-cerebrospinal fluid.
- 2015
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson's disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function.
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| 16. |
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| 17. |
- Benitez, D. P., et al.
(författare)
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Knock-in models related to Alzheimer's disease: synaptic transmission, plaques and the role of microglia
- 2021
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Microglia are active modulators of Alzheimer's disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. Methods App(NL-F) and App(NL-G-F) knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer's disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. Results Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in App(NL-F) mice but was not evident in App(NL-G-F) with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. Conclusions Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer's disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer's disease.
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| 18. |
- Bergström, Sofia, et al.
(författare)
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A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers : a GENFI study
- 2021
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Ingår i: Molecular Neurodegeneration. - : Springer Nature. - 1750-1326. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.
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| 19. |
- Calvo-Rodriguez, Maria, et al.
(författare)
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Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid ß aggregates in vivo in a mouse model of Alzheimer's disease
- 2024
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Ingår i: Molecular Neurodegeneration. - : BMC. - 1750-1326. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundReactive oxidative stress is a critical player in the amyloid beta (A beta) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in A beta plaque-associated dystrophic neurites in the AD brain. Although A beta causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether A beta plaques and soluble A beta oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.MethodsWe expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and A beta plaques.ResultsFor the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both A beta plaque deposition and direct application of soluble oligomeric A beta onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting A beta plaque burden.ConclusionsConsidering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.
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| 20. |
- Chiotis, K., et al.
(författare)
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Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer's disease with multi-modal PET and plasma GFAP
- 2023
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Ingår i: Molecular Neurodegeneration. - 1750-1326. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPlasma assays for the detection of Alzheimer's disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-& beta; burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer 11C-Deuterium-L-Deprenyl (11C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer's disease.MethodsTwenty-four individuals from families with known Autosomal Dominant Alzheimer's Disease mutations (mutation carriers = 10; non-carriers = 14) and fifteen patients with sporadic Alzheimer's disease were included. The individuals underwent PET imaging with 11C-DED, 11C-PIB and 18F-FDG, as markers of reactive astrogliosis, amyloid-& beta; deposition, and glucose metabolism, respectively, and plasma sampling for measuring GFAP concentrations. Twenty-one participants from the Autosomal Dominant Alzheimer's Disease group underwent follow-up plasma sampling and ten of these participants underwent follow-up PET imaging.ResultsIn mutation carriers, plasma GFAP levels and 11C-PIB binding increased, while 11C-DED binding and 18F-FDG uptake significantly decreased across the estimated years to symptom onset. Cross-sectionally, plasma GFAP demonstrated a negative correlation with 11C-DED binding in both mutation carriers and patients with sporadic disease. Plasma GFAP indicated cross-sectionally a significant positive correlation with 11C-PIB binding and a significant negative correlation with 18F-FDG in the whole sample. The longitudinal levels of 11C-DED binding showed a significant negative correlation with longitudinal plasma GFAP concentrations over the follow-up interval.ConclusionsPlasma GFAP concentration and astrocyte 11C-DED brain binding levels followed divergent trajectories and may reflect different underlying processes. The strong negative association between plasma GFAP and 11C-DED binding in Autosomal Dominant and sporadic Alzheimer's disease brains may indicate that if both are markers of reactive astrogliosis, they may detect different states or subtypes of astrogliosis. Increased 11C-DED brain binding seems to be an earlier phenomenon in Alzheimer's disease progression than increased plasma GFAP concentration.
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