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Progressive accumulation of amyloid-β (Aβ) aggregates in extracellular plaques is a characteristic hallmark of Alzheimer disease (AD). Aβ is also found in intraneuronal deposits and associated with alterations of the endo-lysosomal system and impairment of macroautophagy/autophagy. Here, we assessed the effect of Aβ phosphorylation on neuronal autophagy and the endo-lysosomal pathway. Analysis of APP-PSEN1dE9 transgenic mice revealed a phosphorylation-state dependent intraneuronal accumulation of Aβ species in endo-lysosomal and autophagy-related compartments. Cell biological studies further demonstrate a differential uptake and sorting of phosphorylated Aβ variants in cultured neurons, and phosphorylation-state specific effects of Aβ variants on neuronal autophagy and lysosomal function. While Aβ phosphorylated at serine residue 8 accumulated in autophagosomes, Aβ phosphorylated at serine residue 26 showed efficient transport to lysosomes. The selective sorting of phosphorylated Aβ species caused differential impairment of vesicular transport and lysosomal function associated with neurotoxicity. Thus, the relative occurrence of phosphorylated Aβ species and their intraneuronal accumulation could contribute to AD pathogenesis, and to the commonly observed aberrations of the vesicular transport system already at the early stages of the disease. AD: Alzheimer disease; APP: amyloid beta precursor protein; ATG: autophagy related; Aβ: amyloid-β; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; EEA1: early endosome antigen 1; FA: formic acid; GFP: green fluorescent protein; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP2: microtubule-associated protein 2; nmAβ: non-modified amyloid-β; npAβ: non-phosphorylated amyloid-β; pAβ: phosphorylated amyloid-β; p-Ser26Aβ: amyloid-β phosphorylated at serine residue 26; p-Ser8Aβ: amyloid-β phosphorylated at serine residue 8; RAB: RAB, member RAS oncogene family; RFP: red fluorescent protein; SQSTM1/p62: sequestome 1; YFP: yellow fluorescent protein. [ABSTRACT FROM AUTHOR]

A wide range of inherited and acquired conditions can manifest as infantile erythroderma, among which CARD14-associated papulosquamous eruption (CAPE) is a rare cause. An infant boy presented with a psoriasiform rash that progressed to erythroderma and was unresponsive to topical steroids and cyclosporine. The early onset of the disease, its severity and resistance to conventional treatment were suggestive of a genetic cause. Genetic evaluation revealed a homozygous CARD14 variant of uncertain significance establishing the diagnosis of CAPE, and his parents were heterozygous carriers. There was only minimal improvement in the condition with supportive management and treatment with acitretin. Unfortunately, the child succumbed to sepsis and metabolic complications following a sudden worsening of skin disease. This case highlights the significance of genetic studies in diagnosing treatment-refractory cases of infantile erythroderma and emphasises the importance of early recognition of this rare condition. [ABSTRACT FROM AUTHOR]

The characteristics of a sonic under-expanded coaxial jet with lip thickness 1.5Dp (where Dp is the exit diameter of primary jet equals 10 mm) with the primary jet operating at nozzle pressure ratio (NPR) of 3, 4 and 5. For NPR 3 operating primary jet, the secondary jet operates at NPR 2.5, 1.4 and 1.27. For primary jet NPR 4, the secondary jet operating NPR is 3.2, 1.6 and 1.4. For NPR 5 primary jet, the secondary jet NPR is 3.8, 1.89 and 1.52. The study is performed using a co-flow nozzle of bypass ratio (BR) 6.4, 1.4 and 0.7. The core length of the primary jet is used as a measure to quantify the mixing of the primary jet in the presence of coaxial jet. The shock structure present in the near field was viewed using shadowgraph technique. Centreline pitot pressure distribution, radial spread and waves present in the jet core were analyzed. The results show that the mixing associated with the high bypass coaxial jet is superior to the low bypass coaxial jet. This mixing superiority associated with high bypass coaxial jet prevails all levels of expansion. [ABSTRACT FROM AUTHOR]

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimers disease, deposition of amyloid- is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid- and increase the formation of amyloid- oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid- pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid- pathology in transgenic double-mutant APP[sub.Swe]PSEN1[sub.dE9] mice. By contrast, homogenates from brains of APP[sub.Swe]PSEN1[sub.dE9] mice failed to induce seeding and spreading of amyloid- pathology in ASC-deficient APP[sub.Swe]PSEN1[sub.dE9] mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid- pathology in APP[sub.Swe]PSEN1[sub.dE9] mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid- pathology in patients with Alzheimers disease., Author(s): Carmen Venegas [1]; Sathish Kumar [2]; Bernardo S. Franklin [3]; Tobias Dierkes [1, 3]; Rebecca Brinkschulte [3]; Dario Tejera [1]; Ana Vieira-Saecker [1]; Stephanie Schwartz [1]; Francesco Santarelli [1]; [...]