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Highly potent intracellular membrane-associated A? seeds.

ABSTRACT: An early event in Alzheimer's disease (AD) pathogenesis is the formation of extracellular aggregates of amyloid-? peptide (A?), thought to be initiated by a prion-like seeding mechanism. However, the molecular nature and location of the A? seeds remain rather elusive. Active A? seeds are found in crude homogenates of amyloid-laden brains and in the soluble fraction thereof. To analyze the seeding activity of the pellet fraction, we have either separated or directly immunoisolated membranes from such homogenates. Here, we found considerable A? seeding activity associated with membranes in the absence of detectable amyloid fibrils. We also found that A? seeds on mitochondrial or associated membranes efficiently induced A? aggregation in vitro and seed ?-amyloidosis in vivo. A? seeds at intracellular membranes may contribute to the spreading of A? aggregation along neuronal pathways and to the induction of intracellular pathologies downstream of A?.

SUBMITTER: Marzesco AM

PROVIDER: S-EPMC4911570 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Highly potent intracellular membrane-associated Aβ seeds.

Marzesco Anne-Marie AM Flötenmeyer Matthias M Bühler Anika A Obermüller Ulrike U Staufenbiel Matthias M Jucker Mathias M Baumann Frank F

Scientific reports 20160617

An early event in Alzheimer's disease (AD) pathogenesis is the formation of extracellular aggregates of amyloid-β peptide (Aβ), thought to be initiated by a prion-like seeding mechanism. However, the molecular nature and location of the Aβ seeds remain rather elusive. Active Aβ seeds are found in crude homogenates of amyloid-laden brains and in the soluble fraction thereof. To analyze the seeding activity of the pellet fraction, we have either separated or directly immunoisolated membranes from ...[more]

PMID: 27311744

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Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

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Highly potent intracellular membrane-associated A? seeds.

Publications

Highly potent intracellular membrane-associated Aβ seeds.

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