Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease.
An active lifestyle is to some degree protective against Alzheimer's disease (AD), but the biological basis for this benefit is still far from clear. We hypothesize that physical and cognitive activity increase a reserve for plasticity by increasing adult neurogenesis in the hippocampal dentate gyrus (DG). We thus assessed how age affects the response to activity in the murine APP23 model of AD compared with wild type (WT) controls and studied the effects of physical exercise (RUN) and environmental enrichment (ENR) in comparison with standard housing (CTR) at two different ages (6 months and 18 months) and in both genotypes. At 18 months, both activity paradigms reduced the hippocampal human Abeta1-42/Abeta1-40 ratio when compared with CTR, despite a stable plaque load in the hippocampus. At this age, both RUN and ENR increased the number of newborn granule cells in the DG of APP23 mice when compared with CTR, whereas the levels of regulation were equivalent to those in WT mice under the same housing conditions. At 6 months, however, neurogenesis in ENR but not RUN mice responded like the WT. Quantifying the number of cells at the doublecortin-positive stage in relation to the number of cells on postmitotic stages we found that ENR overproportionally increased the number of the DCX-positive "late" progenitor cells, indicative of an increased potential to recruit even more new neurons. In summary, the biological substrates for activity-dependent regulation of adult hippocampal neurogenesis were preserved in the APP23 mice. We thus propose that in this model, ENR even more than RUN might contribute to a "neurogenic reserve" despite a stable plaque load and that age affects the outcome of an interaction based on "activity."
Mirochnic
Sebastian
S
Genomics of Regeneration in CNS, Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany.
Wolf
Susanne
S
Staufenbiel
Matthias
M
Kempermann
Gerd
G
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 / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D004777:Environment; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D006799:Housing, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D058225:Plaque, Amyloid / Q000502:physiology; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D010446:Peptide Fragments; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)