Increased CSF-decorin predicts brain pathological changes driven by Alzheimer's Aβ amyloidosis.

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, App and App, exhibiting AD-like Aβ pathology to analyze how the brain pathologies translate to CSF proteomes by label-free mass spectrometry (MS). This identified several extracellular matrix (ECM) proteins as significantly altered in App knock-in mice.

APP accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in Alzheimer's disease?

In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra-somatic APP, which surround dense-core amyloid plaques enriched in APP-Nter.

Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis.

Mass spectrometry (MS)-based proteomics is a powerful tool to explore pathogenic changes of a disease in an unbiased manner and has been used extensively in Alzheimer disease (AD) research. Here, by performing a meta-analysis of high-quality proteomic studies, we address which pathological changes are observed consistently and therefore most likely are of great importance for AD pathogenesis. We retrieved datasets, comprising a total of 21,588 distinct proteins identified across 857 postmortem human samples, from ten studies using labeled or label-free MS approaches.

Distinctive alteration of presynaptic proteins in the outer molecular layer of the dentate gyrus in Alzheimer's disease.

Synaptic degeneration has been reported as one of the best pathological correlates of cognitive deficits in Alzheimer's disease. However, the location of these synaptic alterations within hippocampal sub-regions, the vulnerability of the presynaptic versus postsynaptic compartments, and the biological mechanisms for these impairments remain unknown. Here, we performed immunofluorescence labelling of different synaptic proteins in fixed and paraffin-embedded human hippocampal sections and report reduced levels of several presynaptic proteins of the neurotransmitter release machinery (complexin-1, syntaxin-1A, synaptotagmin-1 and synaptogyrin-1) in Alzheimer's disease cases.

Proximity ligation assay reveals both pre- and postsynaptic localization of the APP-processing enzymes ADAM10 and BACE1 in rat and human adult brain.

Background: Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the β-secretase BACE1 and by γ-secretase. If APP is instead cleaved by the α-secretase ADAM10, Aβ will not be generated.

The Proteome of the Dentate Terminal Zone of the Perforant Path Indicates Presynaptic Impairment in Alzheimer Disease.

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 synapses of the perforant path, which provides the main excitatory input to the hippocampus. To elucidate the molecular mechanisms underlying the dysfunction of these synapses, we performed an explorative proteomic study of the dentate terminal zone of the perforant path.

Non-specific Detection of a Major Western Blotting Band in Human Brain Homogenates by a Multitude of Amyloid Precursor Protein Antibodies.

The use of human post-mortem brain material is of great value when investigating which pathological mechanisms occur in human brain, and to avoid translational problems which have for example been evident when translating animal research into Alzheimer disease (AD) clinical trials. The amyloid β (Aβ)-peptide, its amyloid precursor protein (APP) and the intermediate APP-c-terminal fragments (APP-CTFs) are all important players in AD pathogenesis. In order to elucidate which APP CTF that are the most common in brain tissue of different species and developmental stages, and whether there are any differences in these fragments between AD and control brain, we investigated the occurrence of these fragments using different APP c-terminal antibodies.

APP depletion alters selective pre- and post-synaptic proteins.

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 of APP has detrimental effects on spines and electrophysiological parameters. APP has been described to be important in synaptic pruning during development.

Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels.

Background: Increased levels of the pathogenic amyloid β-peptide (Aβ), released from its precursor by the transmembrane protease γ-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased in AD brain, but its role in AD pathogenesis is not known. Recent neuroimaging studies have shown that the increased MAO-B expression in AD brain starts several years before the onset of the disease.

Maturation and processing of the amyloid precursor protein is regulated by the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2).

The toxic amyloid β-peptide (Aβ) is a key player in Alzheimer Disease (AD) pathogenesis and selective inhibition of the production of this peptide is sought for. Aβ is produced by the sequential cleavage of the Aβ precursor protein (APP) by β-secretase (to yield APP-C-terminal fragment β (APP-CTFβ) and soluble APPβ (sAPPβ)) and γ-secretase (to yield Aβ). We reasoned that proteins that associate with γ-secretase are likely to regulate Aβ production and to be targets of pharmaceutical interventions and therefore performed a pull-down assay to screen for such proteins in rat brain.

ADAM10 and BACE1 are localized to synaptic vesicles.

Synaptic degeneration and accumulation of the neurotoxic amyloid β-peptide (Aβ) in the brain are hallmarks of Alzheimer disease. Aβ is produced by sequential cleavage of the amyloid precursor protein (APP), by the β-secretase β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. However, Aβ generation is precluded if APP is cleaved by the α-secretase ADAM10 instead of BACE1.

Proton myo-inositol cotransporter is a novel γ-secretase associated protein that regulates Aβ production without affecting Notch cleavage.

γ-Secretase is a transmembrane protease complex that is responsible for the processing of a multitude of type 1 transmembrane proteins, including the amyloid precursor protein and Notch. γ-Secretase processing of amyloid precursor protein results in the release of the amyloid β-peptide (Aβ), which is involved in the pathogenesis in Alzheimer's disease. Processing of Notch leads to the release of its intracellular domain, which is important for cell development.

Activity-independent release of the amyloid β-peptide from rat brain nerve terminals.

Synaptic degeneration is one of the earliest hallmarks of Alzheimer disease. The molecular mechanism underlying this degeneration is not fully elucidated but one key player appears to be the synaptotoxic amyloid β-peptide (Aβ). The exact localization of the production of Aβ and the mechanisms whereby Aβ is released remain elusive.

Erlin-2 is associated with active γ-secretase in brain and affects amyloid β-peptide production.

The transmembrane protease complex γ-secretase is responsible for the generation of the neurotoxic amyloid β-peptide (Aβ) from its precursor (APP). Aβ has a causative role in Alzheimer disease, and thus, γ-secretase is a therapeutic target. However, since there are more than 70 γ-secretase substrates besides APP, selective inhibition of APP processing is required.

Identification of two novel synaptic γ-secretase associated proteins that affect amyloid β-peptide levels without altering Notch processing.

Synaptic degeneration is one of the earliest hallmarks of Alzheimer disease (AD) and results in loss of cognitive function. One of the causative agents for the synaptic degeneration is the amyloid β-peptide (Aβ), which is formed from its precursor protein by two sequential cleavages mediated by β- and γ-secretase. We have earlier shown that γ-secretase activity is enriched in synaptic compartments, suggesting that the synaptotoxic Aβ is produced locally.

Identification of novel γ-secretase-associated proteins in detergent-resistant membranes from brain.

In Alzheimer disease, oligomeric amyloid β-peptide (Aβ) species lead to synapse loss and neuronal death. γ-Secretase, the transmembrane protease complex that mediates the final catalytic step that liberates Aβ from its precursor protein (APP), has a multitude of substrates, and therapeutics aimed at reducing Aβ production should ideally be specific for APP cleavage. It has been shown that APP can be processed in lipid rafts, and γ-secretase-associated proteins can affect Aβ production.

Minor contribution of presenilin 2 for γ-secretase activity in mouse embryonic fibroblasts and adult mouse brain.

γ-Secretase plays an important function in the development of Alzheimer disease, since it participates in the production of the toxic amyloid β-peptide (Aβ) from the amyloid precursor protein (APP). Besides APP, γ-secretase cleaves many other substrates resulting in adverse side effects when γ-secretase inhibitors are used in clinical trials. γ-Secretase is a membrane bound protein complex consisting of at least four subunits, presenilin (PS), nicastrin, Aph-1 and Pen-2.

Mitochondrial γ-secretase participates in the metabolism of mitochondria-associated amyloid precursor protein.

Intracellular amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondria were found to be the target both for amyloid precursor protein (APP) that accumulates in the mitochondrial import channels and for Aβ that interacts with several proteins inside mitochondria and leads to mitochondrial dysfunction. Here, we have studied the role of mitochondrial γ-secretase in processing different substrates.

gamma-Secretase dependent production of intracellular domains is reduced in adult compared to embryonic rat brain membranes.

Background: gamma-Secretase is an intramembrane aspartyl protease whose cleavage of the amyloid precursor protein (APP) generates the amyloid beta-peptide (Abeta) and the APP intracellular domain. Abeta is widely believed to have a causative role in Alzheimer's disease pathogenesis, and therefore modulation of gamma-secretase activity has become a therapeutic goal. Besides APP, more than 50 substrates of gamma-secretase with different cellular functions during embryogenesis as well as adulthood have been revealed.

Synaptic and endosomal localization of active gamma-secretase in rat brain.

Background: A key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (Abeta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to localize primarily to the Golgi apparatus, endosomes and plasma membranes.

Affinity pulldown of γ-secretase and associated proteins from human and rat brain.

γ-Secretase is a transmembrane protease complex responsible for the processing of a multitude of type 1 transmembrane proteins, including amyloid precursor protein (APP) and Notch. A functional complex is dependent on the assembly of four proteins: presenilin (PS), nicastrin, Aph-1 and Pen-2. Little is known about how the substrates are selected by γ-secretase, but it has been suggested that γ-secretase associated proteins (GSAPs) could be of importance.

Active gamma-secretase is localized to detergent-resistant membranes in human brain.

Several lines of evidence suggest that polymerization of the amyloid beta-peptide (Abeta) into amyloid plaques is a pathogenic event in Alzheimer's disease (AD). Abeta is produced from the amyloid precursor protein as the result of sequential proteolytic cleavages by beta-secretase and gamma-secretase, and it has been suggested that these enzymes could be targets for treatment of AD. gamma-Secretase is an aspartyl protease complex, containing at least four transmembrane proteins.

Rat brain gamma-secretase activity is highly influenced by detergents.

Gamma-secretase is important for the development of Alzheimer's disease, since it is a crucial enzyme for the generation of the pathogenic amyloid beta-peptide (Abeta). Most data on gamma-secretase is derived from studies in cell lines overexpressing gamma-secretase components or amyloid precursor protein (APP), and since gamma-secretase is a transmembrane protein complex, detergents have been frequently used to facilitate the studies. However, no extensive comparison of the influence of different detergents at different concentrations on gamma-secretase activity in preparations from brain has been made.

Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria.

Mitochondria are central in the regulation of cell death. Apart from providing the cell with ATP, mitochondria also harbor several death factors that are released upon apoptotic stimuli. Alterations in mitochondrial functions, increased oxidative stress, and neurons dying by apoptosis have been detected in Alzheimer's disease patients.