| 31. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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Proteomics/peptidomics tools to find CSF biomarkers for neurodegenerative diseases.
- 2009
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Ingår i: Frontiers in bioscience : a journal and virtual library. - : IMR Press. - 1093-4715. ; 14, s. 1793-806
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Forskningsöversikt (refereegranskat)abstract
- Neurodegenerative diseases are characterized by premature neuronal loss in specific brain regions. During the past decades our knowledge on molecular mechanisms underlying neurodegeneration has increased immensely and resulted in promising drug candidates that might slow down or even stop the neuronal loss. These advances have put a strong focus on the development of diagnostic tools for early or pre-clinical detection of the disorders. In this review we discuss our experience in the field of neuroproteomics/peptidomics, with special focus on biomarker discovery studies that have been performed on CSF samples from well-defined patient and control populations.
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| 32. |
- Brownjohn, Philip W, et al.
(författare)
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Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.
- 2017
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Ingår i: Stem cell reports. - : Elsevier BV. - 2213-6711. ; 8:4, s. 870-882
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Tidskriftsartikel (refereegranskat)abstract
- Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP) processing and the accumulation of APP-derived amyloid β (Aβ) peptides are key processes in Alzheimer's disease (AD). We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation.
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| 33. |
- Cam, Morgane, et al.
(författare)
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Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides.
- 2018
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 62:4, s. 1663-1681
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Tidskriftsartikel (refereegranskat)abstract
- Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations ofAβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500+compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.
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| 34. |
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| 35. |
- Cummings, Damian M, et al.
(författare)
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First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.
- 2015
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 138:Pt 7, s. 1992-2004
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Tidskriftsartikel (refereegranskat)abstract
- Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease.
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| 36. |
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| 37. |
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| 38. |
- Farid, Karim, et al.
(författare)
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Case Report of Complex Amyotrophic Lateral Sclerosis with Cognitive Impairment and Cortical Amyloid Deposition.
- 2015
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908 .- 1387-2877. ; 47:3, s. 661-7
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS), a fatal disease of unknown origin, affects motor neurons in the primary motor cortex, brainstem, and spinal cord. Cognitive impairment may occur before the motor symptoms. We present a patient who was initially diagnosed with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) but who developed ALS-like symptoms during follow-up and died shortly thereafter. A 60-year-old subject with cognitive impairment underwent neuropsychological testing, cerebrospinal fluid (CSF) analysis, structural imaging (computed tomography and magnetic resonance imaging) and functional imaging [11C]-Pittsburgh compound B (PIB) positron emission tomography (PET), [18F]-fluorodeoxyglucose (FDG) PET, and [11C]-deuterium-L-deprenyl (DED) PET. Neuropsychological testing showed episodic memory impairment. CSF P-tau and T-tau levels were elevated. CSF amyloid-β (Aβ)42 levels were initially normal but became pathological during follow-up. MCI was diagnosed. [18F]-FDG PET showed hypometabolism in the left temporal and prefrontal cortices and [11C]-PIB PET demonstrated amyloid plaque deposition in the prefrontal, posterior cingulate, and parietal cortices. [11C]-DED PET showed high brain accumulation consistent with astrocytosis. The memory impairment progressed and AD was diagnosed. Motor impairments developed subsequently and, following additional neurological evaluation, ALS was diagnosed. The disease progressed rapidly and the patient died with pronounced motor symptoms three years after the initial cognitive assessment. Since relatives refused autopsy, postmortem analysis was not possible.
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| 39. |
- Fourier, Anthony, et al.
(författare)
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Pre-analytical and analytical factors influencing Alzheimer's disease cerebrospinal fluid biomarker variability.
- 2015
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Ingår i: Clinica chimica acta; international journal of clinical chemistry. - : Elsevier BV. - 1873-3492. ; 449, s. 9-15
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Tidskriftsartikel (refereegranskat)abstract
- A panel of cerebrospinal fluid (CSF) biomarkers including total Tau (t-Tau), phosphorylated Tau protein at residue 181 (p-Tau) and β-amyloid peptides (Aβ42 and Aβ40), is frequently used as an aid in Alzheimer's disease (AD) diagnosis for young patients with cognitive impairment, for predicting prodromal AD in mild cognitive impairment (MCI) subjects, for AD discrimination in atypical clinical phenotypes and for inclusion/exclusion and stratification of patients in clinical trials. Due to variability in absolute levels between laboratories, there is no consensus on medical cut-off value for the CSF AD signature. Thus, for full implementation of this core AD biomarker panel in clinical routine, this issue has to be solved. Variability can be explained both by pre-analytical and analytical factors. For example, the plastic tubes used for CSF collection and storage, the lack of reference material and the variability of the analytical protocols were identified as important sources of variability. The aim of this review is to highlight these pre-analytical and analytical factors and describe efforts done to counteract them in order to establish cut-off values for core CSF AD biomarkers. This review will give the current state of recommendations.
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| 40. |
- Fritschi, Sarah K, et al.
(författare)
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Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid.
- 2014
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 137:11, s. 2909-2915
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Tidskriftsartikel (refereegranskat)abstract
- The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-β seeds. In this study, we sought to assess the potency of soluble amyloid-β seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-β deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-β. In contrast, cerebrospinal fluid from patients with Alzheimer's disease, which contained more than 10-fold higher levels of amyloid-β peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-β deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-β species and exhibited smaller amyloid-β-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-β species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid.
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