Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease.
The adult mammalian brain contains populations of stem cells that can proliferate and then differentiate into neurons or glia. The highest concentration of such neural progenitor cells (NPC) is located in the subventricular zone (SVZ) and these cells can produce new olfactory bulb and cerebral cortical neurons. NPC may provide a cellular reservoir for replacement of cells lost during normal cell turnover and after brain injury. However, neurogenesis does not compensate for neuronal loss in age-related neurodegenerative disorders such as Alzheimer's disease (AD), suggesting the possibility that impaired neurogenesis contributes to the pathogenesis of such disorders. We now report that amyloid beta-peptide (Abeta), a self-aggregating neurotoxic protein thought to cause AD, can impair neurogenesis in the SVZ/cerebral cortex of adult mice and in human cortical NPC in culture. The proliferation and migration of NPC in the SVZ of amyloid precursor protein (APP) mutant mice, and in mice receiving an intraventricular infusion of Abeta, were greatly decreased compared to control mice. Studies of NPC neurosphere cultures derived from human embryonic cerebral cortex showed that Abeta can suppress NPC proliferation and differentiation, and can induce apoptosis. The adverse effects of Abeta on neurogenesis were associated with a disruption of calcium regulation in the NPC. Our data show that Abeta can impair cortical neurogenesis, and suggest that this adverse effect of Abeta contributes to the depletion of neurons and the resulting olfactory and cognitive deficits in AD.
Haughey
Norman J
NJ
Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, Baltimore, MD 21224, USA.
Liu
Dong
D
Nath
Avi
A
Borchard
Amy C
AC
Mattson
Mark P
MP
D016229:Amyloid beta-Peptides / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology*; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology
D016229:Amyloid beta-Peptides