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Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease.
J Neurosci Res. 2006 May 15; 83(7):1252-61.JN

Abstract

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.

Authors+Show Affiliations

Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California 92093-0624, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16511867

Citation

Rockenstein, Edward, et al. "Cerebrolysin Decreases Amyloid-beta Production By Regulating Amyloid Protein Precursor Maturation in a Transgenic Model of Alzheimer's Disease." Journal of Neuroscience Research, vol. 83, no. 7, 2006, pp. 1252-61.
Rockenstein E, Torrance M, Mante M, et al. Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease. J Neurosci Res. 2006;83(7):1252-61.
Rockenstein, E., Torrance, M., Mante, M., Adame, A., Paulino, A., Rose, J. B., Crews, L., Moessler, H., & Masliah, E. (2006). Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease. Journal of Neuroscience Research, 83(7), 1252-61.
Rockenstein E, et al. Cerebrolysin Decreases Amyloid-beta Production By Regulating Amyloid Protein Precursor Maturation in a Transgenic Model of Alzheimer's Disease. J Neurosci Res. 2006 May 15;83(7):1252-61. PubMed PMID: 16511867.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease. AU - Rockenstein,Edward, AU - Torrance,Magdalena, AU - Mante,Michael, AU - Adame,Anthony, AU - Paulino,Amy, AU - Rose,John B, AU - Crews,Leslie, AU - Moessler,Herbert, AU - Masliah,Eliezer, PY - 2006/3/3/pubmed PY - 2006/7/26/medline PY - 2006/3/3/entrez SP - 1252 EP - 61 JF - Journal of neuroscience research JO - J. Neurosci. Res. VL - 83 IS - 7 N2 - 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. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/16511867/Cerebrolysin_decreases_amyloid_beta_production_by_regulating_amyloid_protein_precursor_maturation_in_a_transgenic_model_of_Alzheimer's_disease_ L2 - https://doi.org/10.1002/jnr.20818 DB - PRIME DP - Unbound Medicine ER -