Abstract
Alzheimer’s disease (AD) is characterized by extracellular deposition of amyloid-β (Aβ) plaques. These protein deposits impair synaptic plasticity thereby producing a progressive decline in cognitive function. Current therapies are merely palliative and only slow cognitive decline. Poly-N-methylated Aβ-Peptide C-Terminal Fragments (MEPTIDES) were recently shown to reduce Aβ toxicity in vitro and in Drosophila melanogaster, however whether these novel compounds are effective in inhibiting Aβ-induced toxicity in the mammalian brain remains unclear. We therefore investigated whether MEPTIDES have the ability to reduce the neurotoxic effects of Aβ in male Sprague-Dawley (SD) rats. Aβ42 (100 μg, 2 mM) or vehicle (0.15 M Tris buffer) was stereotaxically injected bilaterally into the dorsal hippocampus at a rate of 1 μl/min for 10 min. The effects on hippocampal-mediated learning were subsequently assessed using the Morris water maze (MWM). The presence of apoptotic activity was also assessed by determining the expression levels of active caspase-3 using real-time polymerase chain reaction and Western Blot techniques. In addition, half of the animals (n = 20) received an intraperitoneal (i.p.) injection of MEPTIDES (2 mg/kg) 48 h after intrahippocampal injection of Aβ42. Matrix-assisted laser desorption/ionization-time-of-flight (MALDI –TOF) mass spectrometry (MS) showed that MEPTIDES crossed the blood brain barrier (BBB) and revealed their distribution in the rat brain. Rats treated with Aβ42 displayed spatial learning deficits and increased hippocampal caspase-3 gene (CASP-3) expression which was reversed by subsequent injection of MEPTIDES. The present results show that MEPTIDES have the potential to reverse the toxic effects of Aβ42 in vivo.
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Acknowledgements
The authors acknowledge the technical and editorial assistance by Miss Chloe Eliza Flinn.
This work was supported by the National Research Foundation of South Africa and the University of KwaZulu-Natal, College of Health Sciences.
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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted (ethical clearance no. 048/13/Animal).
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Sibiya, S.G., Mbandla, M.V., Govender, T. et al. Poly-N-methylated Aβ-Peptide C-Terminal fragments (MEPTIDES) reverse the deleterious effects of amyloid-β in rats. Metab Brain Dis 33, 387–396 (2018). https://doi.org/10.1007/s11011-017-0118-x
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DOI: https://doi.org/10.1007/s11011-017-0118-x