by Keyword: amyloid-beta
Seuma M, Lehner B, Bolognesi B, (2022). An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation Nature Communications 13, 7084
Multiplexed assays of variant effects (MAVEs) guide clinical variant interpretation and reveal disease mechanisms. To date, MAVEs have focussed on a single mutation type-amino acid (AA) substitutions-despite the diversity of coding variants that cause disease. Here we use Deep Indel Mutagenesis (DIM) to generate a comprehensive atlas of diverse variant effects for a disease protein, the amyloid beta (Aβ) peptide that aggregates in Alzheimer's disease (AD) and is mutated in familial AD (fAD). The atlas identifies known fAD mutations and reveals that many variants beyond substitutions accelerate Aβ aggregation and are likely to be pathogenic. Truncations, substitutions, insertions, single- and internal multi-AA deletions differ in their propensity to enhance or impair aggregation, but likely pathogenic variants from all classes are highly enriched in the polar N-terminal region of Aβ. This comparative atlas highlights the importance of including diverse mutation types in MAVEs and provides important mechanistic insights into amyloid nucleation.© 2022. The Author(s).
JTD Keywords: amyloid-beta(1-42), determinants, disease, mutants, protein, secondary nucleation, Atomic-resolution structure
Leite, DM, Seifi, M, Ruiz-Perez, L, Nguemo, F, Plomann, M, Swinny, JD, Battaglia, G, (2022). Syndapin-2 mediated transcytosis of amyloid-beta across the blood brain barrier Brain Commun 4, fcac039
A deficient transport of amyloid-beta across the blood-brain barrier, and its diminished clearance from the brain, contribute to neurodegenerative and vascular pathologies, such as Alzheimer's disease and cerebral amyloid angiopathy, respectively. At the blood-brain barrier, amyloid-beta efflux transport is associated with the low-density lipoprotein receptor-related protein 1. However, the precise mechanisms governing amyloid-beta transport across the blood-brain barrier, in health and disease, remain to be fully understood. Recent evidence indicates that the low-density lipoprotein receptor-related protein 1 transcytosis occurs through a tuhulation-mediated mechanism stabilized by syndapin-2. Here, we show that syndapin-2 is associated with amyloid-beta clearance via low-density lipoprotein receptor-related protein 1 across the blood-brain barrier. We further demonstrate that risk factors for Alzheimer's disease, amyloid-beta expression and ageing, are associated with a decline in the native expression of syndapin-2 within the brain endothelium. Our data reveals that syndapin-2-mediated pathway, and its balance with the endosomal sorting, are important for amyloid-beta clearance proposing a measure to evaluate Alzheimer's disease and ageing, as well as a target for counteracting amyloid-beta build-up. Moreover, we provide evidence for the impact of the avidity of amyloid-beta assemblies in their trafficking across the brain endothelium and in low-density lipoprotein receptor-related protein 1 expression levels, which may affect the overall clearance of amyloid-beta across the blood-brain barrier.
JTD Keywords: Alzheimer's disease, Alzheimers-disease, Amyloid-beta, Apolipoprotein-j, Blood-brain barrier, Clearance, Expression, Membrane invagination, Peptide, Protein, Rab gtpases, Receptor, Syndapin-2, Transport, Tubular transcytosis
Ferrer I, Andrés-Benito P, Ausín K, Pamplona R, del Rio JA, Fernández-Irigoyen J, Santamaría E, (2021). Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease Brain Pathology 31,
Tau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I–II, III–IV, and V–VI without comorbidities, and of middle-aged (MA) individuals with no NFT pathology, were analyzed by conventional label-free and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I–II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I–II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III–IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for “benign” cognitive deterioration in “normal” brain aging.
JTD Keywords: (phospho)proteomics, alzheimer's disease, amyloid-beta, association guidelines, brain aging, cytoskeleton, frontal-cortex, kinases, lipid rafts, membranes, national institute, neuropathologic assessment, pathological process, protein phosphorylation, synapse pathology, synapses, tau, tau pathology, (phospho)proteomics, Age-related tauopathy, Alzheimer's disease, Brain aging, Cytoskeleton, Kinases, Membranes, Protein phosphorylation, Synapses, Tau
Lidón L, Llaó-Hierro L, Nuvolone M, Aguzzi A, Ávila J, Ferrer I, Del Río JA, Gavín R, (2021). Tau exon 10 inclusion by prpc through downregulating gsk3? activity International Journal Of Molecular Sciences 22,
Tau protein is largely responsible for tauopathies, including Alzheimer’s disease (AD), where it accumulates in the brain as insoluble aggregates. Tau mRNA is regulated by alternative splicing, and inclusion or exclusion of exon 10 gives rise to the 3R and 4R isoforms respectively, whose balance is physiologically regulated. In this sense, one of the several factors that regulate alternative splicing of tau is GSK3?, whose activity is inhibited by the cellular prion protein (PrPC), which has different physiological functions in neuroprotection and neuronal differentiation. Moreover, a relationship between PrPC and tau expression levels has been reported during AD evolution. For this reason, in this study we aimed to analyze the role of PrPC and the implication of GSK3? in the regulation of tau exon 10 alternative splicing. We used AD human samples and mouse models of PrPC ablation and tau overexpression. In addition, we used primary neuronal cultures to develop functional studies. Our results revealed a paralleled association between PrPC expression and tau 4R isoforms in all models analyzed. In this sense, reduction or ablation of PrPC levels induces an increase in tau 3R/4R balance. More relevantly, our data points to GSK3? activity downstream from PrPC in this phenomenon. Our results indicate that PrPC plays a role in tau exon 10 inclusion through the inhibitory capacity of GSK3?. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
JTD Keywords: alternative splicing, alzheimer's disease, alzheimers-disease, alzheimer’s disease, amyloid-beta, cellular prion protein, frontotemporal dementia, glycogen-synthase kinase-3, gsk3 beta, gsk3?, messenger-rna, microtubule-associated protein tau, neurofibrillary tangles, progressive supranuclear palsy, promotes neuronal differentiation, stem-cells, tauopathies, Alternative splicing, Alzheimer’s disease, Cellular prion protein, Gsk3?, Microtubule-associated protein tau, Tauopathies