A5029984631- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Supramolecular Self-Assembly in Materials
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Bioinformatics and Genomic Networks
- Cellular transport and secretion
- Drug Transport and Resistance Mechanisms
- Mitochondrial Function and Pathology
- Artificial Intelligence in Healthcare
- Computational Drug Discovery Methods
- Prion Diseases and Protein Misfolding
- Conducting polymers and applications
- 14-3-3 protein interactions
- Lipid Membrane Structure and Behavior
- Parkinson's Disease Mechanisms and Treatments
- Intracerebral and Subarachnoid Hemorrhage Research
- Nicotinic Acetylcholine Receptors Study
- Advanced Neuroimaging Techniques and Applications
- S100 Proteins and Annexins
- Nuclear Receptors and Signaling
- Machine Learning in Bioinformatics
- Neuroinflammation and Neurodegeneration Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Advanced biosensing and bioanalysis techniques
Karolinska Institutet
2012-2022
Increased levels of the pathogenic amyloid β-peptide (Aβ), released from its precursor by transmembrane protease γ-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased AD brain, but role pathogenesis not known. Recent neuroimaging studies have shown that MAO-B expression brain starts several years before onset disease. Here, we show a potential connection between MAO-B, γ-secretase and Aβ neurons.MAO-B...
Mitochondria are central in the regulation of cell death. Apart from providing with ATP, mitochondria also harbor several death factors that released upon apoptotic stimuli. Alterations mitochondrial functions, increased oxidative stress, and neurons dying by apoptosis have been detected Alzheimer's disease patients. These findings suggest may trigger abnormal onset neuronal disease. We previously reported presenilin 1 (PS1), which is often mutated familial forms disease, located...
Intracellular amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondria were found to be target both for amyloid precursor protein (APP) that accumulates mitochondrial import channels and Aβ interacts with several proteins inside mitochondria leads dysfunction. Here, we have studied role γ-secretase processing different substrates. We a significant proportion APP is associated cultured cells cleaves shedded C-terminal part identified as C83...
Several lines of evidence suggest that polymerization the amyloid beta-peptide (Abeta) into plaques is a pathogenic event in Alzheimer's disease (AD). Abeta produced from precursor protein as result sequential proteolytic cleavages by beta-secretase and gamma-secretase, it has been suggested these enzymes could be targets for treatment AD. gamma-Secretase an aspartyl protease complex, containing at least four transmembrane proteins. Studies cell have shown gamma-secretase partially localized...
Abstract Synaptic degeneration and accumulation of the neurotoxic amyloid β‐peptide (Aβ) in brain are hallmarks Alzheimer disease. Aβ is produced by sequential cleavage precursor protein (APP), β‐secretase β‐site APP cleaving enzyme 1 (BACE1) γ‐secretase. However, generation precluded if cleaved α‐secretase ADAM10 instead BACE1. We have previously shown that can be locally at synapse. To study synaptic localization processing enzymes we used western blotting to demonstrate that, compared...
Abstract In Alzheimer's disease (AD), the distribution of amyloid precursor protein (APP) and its fragments other than beta, has not been fully characterized. Here, we investigate APP in human AD brain samples mouse models reference to proteases, synaptic proteins, histopathological features characteristic brain, by combining an extensive set histological analytical tools. We report that prominent somatic observed control patients remarkably vanishes benefit dense accumulations extra‐somatic...
Background A key player in the development of Alzheimer's disease (AD) is γ-secretase complex consisting at least four components: presenilin, nicastrin, Aph-1 and Pen-2. γ-Secretase crucial for generation neurotoxic amyloid β-peptide (Aβ) but also takes part processing many other substrates. In cell lines, active has been found to localize primarily Golgi apparatus, endosomes plasma membranes. However, no thorough studies have performed show subcellular localization affected organ AD,...
The normal role of Alzheimer's disease (AD)-linked amyloid precursor protein (APP) in the brain remains incompletely understood. Previous studies have reported that lack APP has detrimental effects on spines and electrophysiological parameters. been described to be important synaptic pruning during development. effect knockout mature synapses is complicated by this We previously differential changes proteins receptors mutant AD transgenic compared wild-type neurons, which revealed selective...
Abstract Background Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks the Alzheimer diseased brain. Aβ is synaptotoxic produced by sequential cleavage precursor protein (APP) β-secretase BACE1 γ-secretase. If APP instead cleaved α-secretase ADAM10, will not be generated. Although considered to a presynaptic ADAM10 has been reported mainly localize postsynaptic density, we have previously shown that both highly enriched in synaptic vesicles rat brain mouse...
Abstract Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimer’s disease (AD) which is characterized by amyloid-β (Aβ) amyloidosis. Here, we used two App knock-in mouse models, NL-F/NL-F and NL-G-F/NL-G-F , exhibiting AD-like Aβ pathology to analyze how the brain pathologies translate CSF proteomes label-free mass spectrometry (MS). This identified several extracellular matrix (ECM) proteins as significantly altered mice. Next, compared with previously reported...
γ-Secretase is a transmembrane protease complex responsible for the processing of multitude type 1 proteins, including amyloid precursor protein (APP) and Notch. A functional dependent on assembly four proteins: presenilin (PS), nicastrin, Aph-1 Pen-2. Little known about how substrates are selected by γ-secretase, but it has been suggested that γ-secretase associated proteins (GSAPs) could be importance. For instance, was recently reported from studies in cell lines TMP21, involved...
Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the of perforant path, which provides main excitatory input hippocampus. To elucidate molecular mechanisms underlying these synapses, we performed explorative proteomic study dentate terminal zone path. The outer two-thirds layer gyrus, where path located, was microdissected from five subjects with...
Synaptic degeneration has been reported as one of the best pathological correlates cognitive deficits in Alzheimer's disease. However, location these synaptic alterations within hippocampal sub-regions, vulnerability presynaptic versus postsynaptic compartments, and biological mechanisms for impairments remain unknown. Here, we performed immunofluorescence labelling different proteins fixed paraffin-embedded human sections report reduced levels several neurotransmitter release machinery...
The use of human post-mortem brain material is great value when investigating which pathological mechanisms occur in brain, and to avoid translational problems have for example been evident translating animal research into Alzheimer disease (AD) clinical trials. amyloid β (Aβ)-peptide, its precursor protein (APP) the intermediate APP-c-terminal fragments (APP-CTFs) are all important players AD pathogenesis. In order elucidate APP CTF that most common tissue different species developmental...
γ-Secretase is important for the development of Alzheimer's disease, since it a crucial enzyme generation pathogenic amyloid β-peptide (Aβ). Most data on γ-secretase derived from studies in cell lines overexpressing components or precursor protein (APP), and transmembrane complex, detergents have been frequently used to facilitate studies. However, no extensive comparison influence different at concentrations activity preparations brain has made. Here, we establish optimal conditions rat...
The deposition of the Aβ is a pathogenic event in Alzheimer's disease and γ-secretase responsible for final cleavage amyloid precursor protein to generate Aβ. γ-Secretase transmembrane (TM) aspartyl protease complex which catalyzes type I TM proteins, including APP Notch. Four proteins: PS, Nct, Aph-1 Pen-2 are necessary sufficient an active complex, but little known about how regulated. Other associated proteins may affect activity, studies cell lines have shown that TMP21, CD147 many other...
Background γ-Secretase is an intramembrane aspartyl protease whose cleavage of the amyloid precursor protein (APP) generates β-peptide (Aβ) and APP intracellular domain. Aβ widely believed to have a causative role in Alzheimer's disease pathogenesis, therefore modulation γ-secretase activity has become therapeutic goal. Besides APP, more than 50 substrates with different cellular functions during embryogenesis as well adulthood been revealed. Prior cleavage, are ectodomain shedded, producing...