Cerebrolysin decreases amyloid-β production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease

Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California 92093-0624, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 05/2006; 83(7):1252-61. DOI: 10.1002/jnr.20818
Source: PubMed


Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.

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    • "This compound is a neuropeptide preparation consisting of low-molecular-weight peptides and free amino acids. This compound mimics the action of endogenous neurotrophic factors, and it is postulated that a mixture of this peptide with neurotrophic effects may reduce neurodegenerative pathologies (Rockenstein et al., 2006). Wei et al. proposed that the main effects of Cerebrolysin include neurotrophic stimulation, neuroimmunological regulation and the improvement of glucose transportation across blood-brain barrier (Wei et al., 2007). "
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    • "CBL has previously been reported to decrease Aβ production in APP tg mice by regulating the maturation of the amyloid protein precursor (Rockenstein et al. 2006) and to decrease amyloid deposition around the cerebrovasculature (Rockenstein et al. 2005a) however our results indicate that whilst behavior analysis in the water maze test demonstrated a sustained beneficial effect of CBL up to 3 months after the cessation of treatment, neocortical amyloid plaque load in the TPT 3m CBL-treated APP tg mice was comparable to that observed in the saline-treated APP tg mice at this age indicating that,at TPT 3m, the beneficial effect of CBL, whilst still leading to improved behavioral performance, did not extend to a continued reduction in Aβ plaques. Although there was a slight, but significant, decrease in hippocampal amyloid plaques at TPT 3m in the CBL-treated APP tg mice, the reduction in Aβ deposition at this time point was nowhere near as dramatic as that observed at TPT 0m. "
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    • "These plastic changes included the enhancement in both the dendritic spine density and dendritic length. In agreement with the present results, i.p. administration of Cbl enhanced DG neurogenesis, synaptophysin immunoreactivity and density of glutamate receptor subunit 1 in hippocampus and improved the spatial learning and memory of aged rats (Eder et al., 2001; Francis-Turner and Valousková , 1996; Gschanes and Windisch, 1999; Reinprecht et al., 1999; Tatebayashi et al., 2003), reduced the amyloid burden in the frontal cortex of 5-month-old APP transgenic mice (Rockenstein et al., 2006) and improved the motor function in rats and transgenic mice (Doppler et al., 2008; Sharma et al., 2010a, 2010b). "
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