The dentate gyrus neurogenesis: a therapeutic target for Alzheimer's disease.
Neurogenesis persists in the aged human dentate gyrus but its role and regulation in pathological conditions such as Alzheimer's disease (AD), where the neurotrophic environment is changed, are poorly understood. In this study we investigated the effect of changes in the neurotrophic environment on neurogenesis in cultured rat hippocampal progenitors and in normal adult rats as models. In hippocampal progenitor cells from adult rats, fibroblast growth factor-2 (FGF-2) dose-dependently decreased microtubule-associated protein 2 and increased tau levels, indicating an FGF-2-induced dendrite to axon polarity shift. Cerebrolysin, a neurotrophic drug which has been shown to improve cognition and mood of AD patients, was found to increase neuron-like differentiated adult rat hippocampal progenitors in culture both by reducing apoptosis and by counteracting the FGF-2-induced polarity shift. Intraperitoneal administration of Cerebrolysin enhanced dentate gyrus neurogenesis and maze performance of 8- to 12-month-old female rats. These studies suggest that AD pathogenesis might involve an abnormally elevated FGF-2-associated dysregulation of dentate gyrus neurogenesis, especially neuronal polarity and that the neurogenesis pathology is a promising therapeutic target for this disease.
Tatebayashi
Yoshitaka
Y
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA.
Lee
Moon H
MH
Li
Liang
L
Iqbal
Khalid
K
Grundke-Iqbal
Inge
I
D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology*; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007150:Immunohistochemistry; D018782:Maze Learning / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D016875:tau Proteins / Q000187:drug effects
D000596:Amino Acids; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D016875:tau Proteins; D016222:Fibroblast Growth Factor 2; C006952:cerebrolysin