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Publikation

Steffen, J.; Krohn, M.; Schwitlick, C.; Brüning, T.; Paarmann, K.; Pietrzik, C. U.; Biverstål, H.; Jansone, B.; Langer, O.; Pahnke, J.; Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice Acta Neuropathol. Commun. 5, 49, (2017) DOI: 10.1186/s40478-017-0448-2

Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer’s disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.
Publikation

Sike, ?.; Wengenroth, J.; Upīte, J.; Brüning, T.; Eiriz, I.; Sántha, P.; Biverstål, H.; Jansone, B.; Haugen, H. J.; Krohn, M.; Pahnke, J.; Improved method for cannula fixation for long-term intracerebral brain infusion J. Neurosci. Meth. 290, 145-150, (2017) DOI: 10.1016/j.jneumeth.2017.07.026

BackgroundImplanted osmotic minipumps are commonly used for long-term, brain-targeted delivery of a wide range of experimental agents by being connected to a catheter and a cannula. During the stereotactical surgery procedure, the cannula has to be placed correctly in the x-y directions and also with respect to the injection point in the z-direction (deepness). However, the flat fixation base of available cannula holders doesn’t allow an easy, secure fixation onto the curve-shaped skull.New methodWe have developed a modified method for a better fixation of the cannula holder by using an easy-to-produce, skull-shaped silicone spacer as fixation adapter.ResultsWe describe the application and its fast and reliable production in the lab.Comparison with existing method(s)Superglue or cement is currently being used as the method of choice. However, the curve-shaped skull surface does not fit well with the flat and rigid cannula adapter which leads to fixation problems over time causing wide infusion channels and often also to leakage problems from intracerebrally applied agents towards the surface meninges. As another consequence of the inappropriate fixation, the cannula may loosen from the skull before the end of the experiment or it causes damage to the brain tissue, harming the animals with leading to a failure of the whole experiment.ConclusionsThe easy-to-produce spacer facilitates the crucial step of long-term, stereotactic brain infusion experiments with intracerebral catheters in a highly secure and reproducible way.
Publikation

Aleksis, R.; Oleskovs, F.; Jaudzems, K.; Pahnke, J.; Biverstål, H.; Structural studies of amyloid-β peptides: Unlocking the mechanism of aggregation and the associated toxicity Biochimie 140, 176-192, (2017) DOI: 10.1016/j.biochi.2017.07.011

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. Formation of amyloid plaques consisting of amyloid-β peptides (Aβ) is one of the hallmarks of AD. Several lines of evidence have shown a correlation between the Aβ aggregation and the disease development. Extensive research has been conducted with the aim to reveal the structures of the neurotoxic Aβ aggregates. However, the exact structure of pathological aggregates and mechanism of the disease still remains elusive due to complexity of the occurring processes and instability of various disease-relevant Aβ species. In this article we review up-to-date structural knowledge about amyloid-β peptides, focusing on data acquired using solution and solid state NMR techniques. Furthermore, we discuss implications from these structural studies on the mechanisms of aggregation and neurotoxicity.

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