Development and mechanism of ?-secretase modulators for Alzheimer's disease.
AuthorsCrump CJ, Johnson DS, Li YM
JournalBiochemistry
PubMed ID23614767
'?-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1, and Pen2 with 19 transmembrane domains. ?-Secretase cleaves the amyloid precursor proteins (APP) to release Aß peptides that likely play a causative role in the pathogenesis of Alzheimer's disease (AD). In addition, ?-secretase cleaves Notch and other type I ... More
Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer's disease patients and healthy controls.
AuthorsKvartsberg H, Portelius E, Andreasson U, Brinkmalm G, Hellwig K, Lelental N, Kornhuber J, Hansson O, Minthon L, Spitzer P, Maler JM, Zetterberg H, Blennow K, Lewczuk P
Journal
PubMed ID26136856
'Synaptic dysfunction and degeneration are central events in Alzheimer''s disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 ... More
Brain amyloid-beta fragment signatures in pathological ageing and Alzheimer's disease by hybrid immunoprecipitation mass spectrometry.
AuthorsPortelius E, Lashley T, Westerlund A, Persson R, Fox NC, Blennow K, Revesz T, Zetterberg H
Journal
PubMed ID25591542
'Senile plaques in Alzheimer''s disease (AD) are composed of amyloid-ß (Aß), especially N-truncated forms including Aß4-42. These are thought to be neurotoxic. However, individuals may live for decades with biomarker evidence of cerebral ß-amyloidosis (positive amyloid PET imaging and/or low cerebrospinal fluid levels of the 42 amino acid form of ... More
Pyroglutamate amyloid ß (Aß) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease.
AuthorsWittnam JL, Portelius E, Zetterberg H, Gustavsson MK, Schilling S, Koch B, Demuth HU, Blennow K, Wirths O, Bayer TA
JournalJ Biol Chem
PubMed ID22267726
'Pyroglutamate-modified Aß peptides at amino acid position three (Aß(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aß(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the ... More
APP metabolism regulates tau proteostasis in human cerebral cortex neurons.
AuthorsMoore S, Evans LD, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K, Hardy J, Zetterberg H, Livesey FJ
Journal
PubMed ID25921538
'Accumulation of Aß peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer''s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of ... More
Cerebrospinal fluid biomarkers of ß-amyloid metabolism in multiple sclerosis.
AuthorsAugutis K, Axelsson M, Portelius E, Brinkmalm G, Andreasson U, Gustavsson MK, Malmeström C, Lycke J, Blennow K, Zetterberg H, Mattsson N
JournalMult Scler
PubMed ID23069872
Amyloid precursor protein (APP) and amyloid ß (Aß) peptides are intensely studied in neuroscience and their cerebrospinal fluid (CSF) measurements may be used to track the metabolic pathways of APP in vivo. Reduced CSF levels of Aß and soluble APP (sAPP) fragments are reported in inflammatory diseases, including multiple sclerosis ... More
The luminal Vps10p domain of sortilin plays the predominant role in targeting to insulin-responsive Glut4-containing vesicles.
AuthorsShi J, Kandror KV,
JournalJ Biol Chem
PubMed ID17220298
In fat and skeletal muscle cells, insulin-responsive vesicles, or IRVs, deliver glucose transporter Glut4 and several associated proteins to the plasma membrane in response to hormonal stimulation. Although the protein composition of the IRVs is well studied, the mechanism of their formation is unknown. It is believed, however, that the ... More
Highly specific and sensitive measurements of human and monkey interleukin 21 using sequential protein and tryptic peptide immunoaffinity LC-MS/MS.
AuthorsPalandra J, Finelli A, Zhu M, Masferrer J, Neubert H
JournalAnal Chem
PubMed ID23638938
A highly specific and sensitive immunoaffinity LC-MS/MS assay for quantification of human and cynomolgus monkey interleukin 21 (IL-21) was developed, qualified, and implemented. The workflow includes offline enrichment of IL-21 using an anti-IL-21 capture antibody, followed by isolation using magnetic beads, trypsin digestion, online enrichment of IL-21 derived tryptic peptides ... More
Highly potent soluble amyloid-ß seeds in human Alzheimer brain but not cerebrospinal fluid.
AuthorsFritschi SK, Langer F, Kaeser SA, Maia LF, Portelius E, Pinotsi D, Kaminski CF, Winkler DT, Maetzler W, Keyvani K, Spitzer P, Wiltfang J, Kaminski Schierle GS, Zetterberg H, Staufenbiel M, Jucker M
Journal
PubMed ID25212850
The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-ß seeds. In this study, we sought to assess the potency of soluble amyloid-ß seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the ... More
SorLA complement-type repeat domains protect the amyloid precursor protein against processing.
AuthorsMehmedbasic A, Christensen SK, Nilsson J, Rüetschi U, Gustafsen C, Poulsen AS, Rasmussen RW, Fjorback AN, Larson G, Andersen OM
Journal
PubMed ID25525276
SorLA is a neuronal sorting receptor that is genetically associated with Alzheimer disease. SorLA interacts directly with the amyloid precursor protein (APP) and affects the processing of the precursor, leading to a decreased generation of the amyloid-ß peptide. The SorLA complement-type repeat (CR) domains associate in vitro with APP, but ... More
Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease.
Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aß), one of the pathological hallmarks of AD, can be altered with high levels of physical activity. ... More
Targeting LAMP2 in human cerebrospinal fluid with a combination of immunopurification and high resolution parallel reaction monitoring mass spectrometry.
AuthorsSjödin S, Öhrfelt A, Brinkmalm G, Zetterberg H, Blennow K, Brinkmalm A
JournalClin Proteomics
PubMed ID26924951
Alzheimer's disease is the most common form of dementia. An increasing body of evidence suggests that endo-lysosomal dysfunction is a pathogenic mechanism of Alzheimer's disease. Thus there is a potential for proteins involved in the normal function of endo-lysosomal vesicles to act as biomarkers of disease. Herein we focused on ... More