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P4–299: Cerebrolysin decreases amyloid–β production by regulating APP maturation in a transgenic model of Alzheimer's disease
Author(s) -
Moessler Herbert,
Rockenstein Edward,
Masliah Eliezer
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2038
Subject(s) - cerebrolysin , amyloid precursor protein , cyclin dependent kinase 5 , senile plaques , neuroprotection , gsk 3 , genetically modified mouse , chemistry , kinase , amyloid precursor protein secretase , alzheimer's disease , microbiology and biotechnology , biochemistry , biology , transgene , pharmacology , medicine , protein kinase a , neuroscience , mitogen activated protein kinase kinase , disease , gene
Background: CerebrolysinTM 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 precursor protein (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. Objective(s): Cerebrolysin might reduce amyloid deposition by regulating amyloid(A ) degradation or by modulating APP expression, maturation or processing. These possibilities were investigated in these studies. Methods: APP tg mice were treated for six 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, -secretase (BACE1), and A -degrading enzymes (Neprilysin [Nep] and insulin degrading enzyme [IDE]). Results: 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 (CTFs); however, levels of BACE1, Notch1, Nep and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3 (GSK3 ) (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. Conclusions: 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 Ab protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce A production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.