Abeta(1-42) stimulates adult SVZ neurogenesis through the p75 neurotrophin receptor.
The generation of amyloid-beta peptide (Abeta) and its accumulation in amyloid plaques are generally recognized as key characteristics of Alzheimer's disease. A number of reports have indicated that Abeta can regulate the proliferation of neural precursor cells and adult neurogenesis, suggesting that this may underpin the cognitive decline and compromised olfaction also associated with the condition. Here we report that Abeta(1-42) treatment both in vitro and in vivo, as well as endogenous generation of Abeta in C100 and APP/PS1 transgenic models of Alzheimer's disease, stimulate neurogenesis of young adult subventricular zone precursors. The neurogenic effect of Abeta(1-42) was found to require expression of the p75 neurotrophin receptor (p75(NTR)) by the precursor cells, and activation of p75(NTR) by metalloprotease cleavage. However, precursors from 12-month-old APP/PS1 mice failed to respond to Abeta(1-42). Our results suggest that overstimulation of p75(NTR)-positive progenitors during early life might result in depletion of the stem cell pool and thus a more rapid decline in basal neurogenesis. This, in turn, could lead to impaired neurogenic function in later life.
Sotthibundhu
Areechun
A
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
Li
Qiao-Xin
QX
Thangnipon
Wipawan
W
Coulson
Elizabeth J
EJ
D053687:Adult Stem Cells / Q000502:physiology*; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000502:physiology* / Q000503:physiopathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D055153:Stem Cell Niche / Q000502:physiology* / Q000503:physiopathology
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C075222:amyloid beta-protein (1-42); D045726:Metalloproteases