Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Aβ peptides (mainly Aβ1-40 and Aβ1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4-x peptides being particularly abundant. Aβ4-x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aβ peptide sequence, which facilitates Aβ4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4-40 but unchanged levels of Aβ1-x peptides. In the 5xFAD mouse model of amyloidosis, Aβ4-x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4 −/− knockout background, Aβ4-40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aβ species, but Aβ4-40 peptides were absent in cultures derived from ADAMTS4 −/− mice indicating that the enzyme was essential for Aβ4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aβ4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aβ peptides.
BackgroundThe deposition of neurotoxic amyloid-β (Aβ) peptides in plaques in the brain parenchyma and in cerebral blood vessels is considered to be a key event in Alzheimer’s disease (AD) pathogenesis. Although the presence and impact of full-length Aβ peptides such as Aβ1–40 and Aβ1–42 have been analyzed extensively, the deposition of N-terminally truncated Aβ peptide species has received much less attention, largely because of the lack of specific antibodies.MethodsThis paper describes the generation and characterization of novel antibodies selective for Aβ4–x peptides and provides immunohistochemical evidence of Aβ4–x in the human brain and its distribution in the APP/PS1KI and 5XFAD transgenic mouse models.ResultsThe Aβ4–x staining pattern was restricted mainly to amyloid plaque cores and cerebral amyloid angiopathy in AD and Down syndrome cases and in both AD mouse models. In contrast, diffuse amyloid deposits were largely negative for Aβ4–x immunoreactivity. No overt intraneuronal staining was observed.ConclusionsThe findings of this study are consistent with previous reports demonstrating a high aggregation propensity of Aβ4–x peptides and suggest an important role of these N-truncated Aβ species in the process of amyloidogenesis and plaque core formation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0309-z) contains supplementary material, which is available to authorized users.
The environmental enrichment (EE) paradigm is regarded as a useful tool to create a physical and intellectual stimulation for laboratory rodents and has been used in a variety of Alzheimer disease (AD) mouse models. However, the results of these studies have been conflicting as EE had inconsistent effects on memory performance, Aβ deposition, inflammatory status and other pathological outcomes depending on the AD model. Here, we studied the influence of a lifelong EE on the widely used 5XFAD mouse model, representing the main pathological features of AD. Although 11 months of enriched housing led to an improved survival rate and a partial rescue of motor performance, no beneficial effects in terms of anxiety phenotype, working memory performance, Aβ plaque load, Aβ levels, endogenous APP processing and inflammatory status were observed in 5XFAD mice. Concordantly, no changes in expression levels of BACE1 or Aβ-degrading enzymes like neprilysin or insulin-degrading enzyme could be detected in active mice. The 5XFAD model develops a relatively fast and aggressive pathology and therefore presents a model for early onset familial AD. Our results suggest that an intervention like EE might be too mild to counteract the fast disease progression seen in this model. Therefore, our data provide evidence that the effects of physical and cognitive stimulation vary depending on the severity of the pathology of the model and therefore might be more beneficial in models developing a milder AD phenotype.
In 2000, the World Health Organization (WHO) published an ultrasound field protocol for assessing morbidity due to schistosomiasis. The present study aims to review the acceptance of the WHO protocol for Schistosoma haematobium. A PubMed literature research using the keywords "ultrasound OR ultrasonography (US) AND schistosomiasis," "US AND S. haematobium," "US AND urinary schistosomiasis" from 2001 through 2014 was performed. Thirty-eight eligible publications reporting on 17,861 patients from 13 endemic and 2 non-endemic countries were analysed. Of these, 33 referred to field studies on 17,317 patients. The Niamey protocol was applied to 15,367/17,317 (88.74%) patients in 23/33 (69.70%) of field studies (all studies: 15,649/17,861 [87.61%] patients (25/38 [68.42%] studies). The acceptance of the protocol by single country in field studies varied from 0 to 100%. It varied over time between 55.56% (5/9) in the period from 2001 to 2004, to 87.50% (7/8) from 2005 to 2008, to 62.50% (5/8) from 2009 to 2011 and 75.00% (6/8) from 2012 through 2014 (all studies: 50% [5/10], 88.89% [8/9], 62.50% [5/8], 63.64% [7/11], respectively). The Niamey protocol was applied also in 2/5 hospital studies in 282/544 (51.84%) patients.The usefulness of the WHO protocol for S. haematobium infections is confirmed by its worldwide acceptance. Some simplifications might facilitate its use also for focused ultrasound examinations performed by less skilled examiners. Organ abnormalities due to schistosomiasis detectable by ultrasonography not yet covered by the WHO protocol should be added to the additional investigations section.
Malaria recurrences after an initially successful therapy and malarial fever occurring a long time after infection are well-known problems in malariology. Currently, two distinct types of malaria recurrences are defined: recrudescence and relapse. A recrudescence is thought to originate from circulating Plasmodium blood stages which do not cause fever before a certain level of a microscopically detectable parasitemia is reached. Contrary, a relapse is thought to originate from quiescent intracellular hepatic parasite stages called hypnozoites. Recrudescences would typically occur in infections due to Plasmodium falciparum. Plasmodium knowlesi, and Plasmodium malariae, whereas relapses would be caused exclusively by Plasmodium vivax and Plasmodium ovale. This schematic view is, however, insufficiently supported by experimental evidence. For instance, hypnozoites of P. ovale have never been experimentally documented. On the other hand, the nonfinding of P. malariae hypnozoites turned into the proof for the nonexistence of P. malariae hypnozoites. Clinical relapse-type recurrences have been observed in both P. ovale and P. malariae infections, and decade-long incubation times have also been reported in P. falciparum infections. We propose a gradual hypothesis in accordance with the continuity concept of biological evolution: both, relapse and recrudescence may be potentially caused by all Plasmodium spp. We hypothesize that the difference between the various Plasmodium spp. is quantitative rather than qualitative: there are Plasmodium spp. which frequently cause relapses such as P. vivax, particularly the P.v. Chesson strain, species which cause relapses less frequently, such as P. ovale and sometimes P. malariae, and species which may exceptionally cause relapses such as P. falciparum. All species may cause recrudescences. As clinical consequences, we propose that 8-aminquinolines may be considered in a relapse-type recrudescence regardless of the causal Plasmodium sp., whereas primaquine relapse prevention might not be routinely indicated in malaria due to P. ovale.
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