Effects of Cerebrolysin on neurogenesis in an APP transgenic model of Alzheimer's disease.
Cerebrolysin (CBL) is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative alterations in Alzheimer's disease (AD). We have previously shown that in the amyloid precursor protein (APP) transgenic (tg) mouse model of AD, CBL improves synaptic plasticity and behavioral performance. However, the mechanisms are not completely clear. The neuroprotective effects of CBL might be related to its ability to promote neurogenesis in the hippocampal subgranular zone (SGZ) of the dentate gyrus (DG). To study this possibility, tg mice expressing mutant APP under the Thy-1 promoter were injected with BrdU and treated with CBL for 1 and 3 months. Compared to non-tg controls, vehicle-treated APP tg mice showed decreased numbers of BrdU-positive (+) and doublecortin+ (DCX) neural progenitor cells (NPC) in the SGZ. In contrast, APP tg mice treated with CBL showed a significant increase in BrdU+ cells, DCX+ neuroblasts and a decrease in TUNEL+ and activated caspase-3 immunoreactive NPC. CBL did not change the number of proliferating cell nuclear antigen+ (PCNA) NPC or the ratio of BrdU+ cells converting to neurons and astroglia in the SGZ cells in the APP tg mice. Taken together, these studies suggest that CBL might rescue the alterations in neurogenesis in APP tg mice by protecting NPC and decreasing the rate of apoptosis. The improved neurogenesis in the hippocampus of CBL-treated APP tg mice might play an important role in enhancing synaptic formation and memory acquisition.
Rockenstein
Edward
E
Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, 92093-0624, USA.
Mante
Michael
M
Adame
Anthony
A
Crews
Leslie
L
Moessler
Herbert
H
Masliah
Eliezer
E
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000596:Amino Acids / Q000627:therapeutic use*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013997:Time Factors
D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D018809:Proliferating Cell Nuclear Antigen; C006952:cerebrolysin; D001973:Bromodeoxyuridine