Background
In aging mice, activity maintains hippocampal plasticity and adult hippocampal neurogenesis
at a level corresponding to a younger age. Here we studied whether physical exercise
and environmental enrichment would also affect brain plasticity in a mouse model of
Alzheimer’s disease (AD).
Methods
Amyloid precursor protein (APP)-23 mice were housed under standard or enriched conditions
or in cages equipped with a running wheel. We assessed β-amyloid plaque load, adult
hippocampal neurogenesis, spatial learning, and mRNA levels of trophic factors in
the brain.
Results
Despite stable β-amyloid plaque load, enriched-living mice showed improved water maze
performance, an up-regulation of hippocampal neurotrophin (NT-3) and brain-derived
neurotrophic factor (BDNF) and increased hippocampal neurogenesis. In contrast, despite
increased bodily fitness, wheel-running APP23 mice showed no change in spatial learning
and no change in adult hippocampal neurogenesis but a down-regulation of hippocampal
and cortical growth factors.
Conclusions
We conclude that structural and molecular prerequisites for activity-dependent plasticity
are preserved in mutant mice with an AD-like pathology. Our study might help explain
benefits of activity for the aging brain but also demonstrates differences between
physical and more cognitive activity. It also suggests a possible cellular correlate
for the dissociation between structural and functional pathology often found in AD.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The exercise-induced expression of BDNF within the hippocampus varies across life-span.Neurobiol Aging. 2005; 26: 511-520
- Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease.J Neurosci. 2005; 25: 4217-4221
- Protective effects of insulin-like growth factor-I on the somatostatinergic system in the temporal cortex of beta-amyloid-treated rats.J Neurochem. 2005; 92: 607-615
- Environmental enrichment improves cognition in aged Alzheimer’s transgenic mice despite stable beta-amyloid deposition.Neuroreport. 2004; 15: 1751-1754
- Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain.J Neurosci. 2001; 21: 6718-6731
- Problems in the study of rodent aggression.Horm Behavior. 2003; 44: 161-170
- Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice.J Neurosci. 2002; 22: 515-522
- Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.Neuron. 1997; 19: 939-945
- Transient calretinin-expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice.Mol Cell Neurosci. 2003; 24: 603-613
- Transient expression of doublecortin during adult neurogenesis.J Comp Neurol. 2003; 467: 1-10
- Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone.Development. 2004; 131: 2173-2181
- Neuron loss in APP transgenic mice.Nature. 1998; 395: 755-756
- VEGF links hippocampal activity with neurogenesis, learning and memory.Nat Genet. 2004; 36: 827-835
- The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer’s disease.Eur J Pharmacol. 2004; 490: 127-133
- Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy.J Neurosci. 2001; 21: 5678-5684
- Cardiovascular fitness, cortical plasticity, and aging.Proc Natl Acad Sci U S A. 2004; 101: 3316-3321
- Neurocognitive aging and cardiovascular fitness: recent findings and future directions.J Mol Neurosci. 2004; 24: 9-14
- Controlling neural stem cell division within the adult subventricular zone: an APPealing job.Trends Neurosci. 2005; 28: 57-59
- Doublecortin expression levels in adult brain reflect neurogenesis.Eur J Neurosci. 2005; 21: 1-14
- An autopsy-verified study of the effect of education on degenerative dementia.Brain. 1999; 122: 2309-2319
- Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date.Mol Psychiatry. 2003; 8: 974-982
- Spatial learning and exploration of environmental stimuli in 24-month-old female APP23 transgenic mice with the Swedish mutation.Brain Res. 2004; 1024: 113-121
- Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex.Cereb Cortex. 2003; 13: 845-851
- Paradoxical effects of learning the Morris water maze on adult hippocampal neurogenesis in mice may be explained by a combination of stress and physical activity.Genes Brain Behav. 2006; 5: 29-39
- VEGF is necessary for exercise-induced adult hippocampal neurogenesis.Eur J Neurosci. 2003; 18: 2803-2812
- Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment.Neurosci Lett. 1992; 138: 153-156
- Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.Neuroscience. 2004; 124: 71-79
- An active and socially integrated lifestyle in late life might protect against dementia.Lancet Neurol. 2004; 3: 343-353
- Patients with Alzheimer’s disease have reduced activities in midlife compared with healthy control-group members.Proc Natl Acad Sci U S A. 2001; 98: 3440-3445
- Physical exercise induces FGF-2 and its mRNA in the hippocampus.Brain Res. 1997; 764: 1-8
- Learning enhances adult neurogenesis in the hippoampal formation.Nat Neurosci. 1999; 2: 260-265
- Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function.Neuroscience. 2004; 125: 129-139
- 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.Neuromolecular Med. 2002; 1: 125-135
- Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease.J Neurochem. 2002; 83: 1509-1524
- Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain.Exp Neurol. 2000; 164: 45-52
- Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development.Curr Neurol Neurosci Rep. 2002; 2: 457-464
- Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease.J Neuropathol Exp Neurol. 2003; 62: 1220-1227
- Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells.Exp Neurol. 2005; 196: 342-351
- Enhanced neurogenesis in Alzheimer’s disease transgenic (PDGF-APPSw,Ind) mice.Proc Natl Acad Sci U S A. 2004; 101: 13363-13367
- Increased hippocampal neurogenesis in Alzheimer’s disease.Proc Natl Acad Sci U S A. 2004; 101: 343-347
- Education and the prevalence of dementia and Alzheimer’s disease.Neurology. 1993; 43: 13-20
- Clinical trials in Alzheimer disease: debate on the use of placebo controls.Alzheimer Dis Assoc Disord. 1999; 13: 124-129
- Progressive age-related impairment of cognitive behavior in APP23 transgenic mice.Neurobiol Aging. 2003; 24: 365-378
- Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment.Ann Neurol. 2002; 52: 135-143
- Milestones of neuronal development in the adult hippocampus.Trends Neurosci. 2004; 27: 447-452
- More hippocampal neurons in adult mice living in an enriched environment.Nature. 1997; 386: 493-495
- Experience-induced neurogenesis in the senescent dentate gyrus.J Neurosci. 1998; 18: 3206-3212
Kronenberg G, Bick-Sander A, Bunk E, Wolf C, Ehninger D, Kempermann G (2005): Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol Aging (Epub ahead of print).
- Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli.J Comp Neurol. 2003; 467: 455-463
- Magnetic resonance angiography and vascular corrosion casting as tools in biomedical research: application to transgenic mice modeling Alzheimer’s disease.Neurol Res. 2004; 26: 507-516
- Actions and interactions of the IGF system in Alzheimer’s disease: review and hypotheses.Growth Horm IGF Res. 2000; 10: 1-13
- Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation.Brain Res. 2002; 956: 36-44
- Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats.J Cereb Blood Flow Metab. 1999; 19: 1220-1228
- Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice.Cell. 2005; 120: 701-713
- Are sex and educational level independent predictors of dementia and Alzheimer’s disease? Incidence data from the PAQUID project.J Neurol Neurosurg Psychiatry. 1999; 66: 177-183
- Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis.Neuroscience. 2001; 107: 603-613
- Exercise level and cognitive decline: the MoVIES project.Alzheimer Dis Assoc Disord. 2004; 18: 57-64
- Early-life risk factors and the development of Alzheimer’s disease.Neurology. 2000; 54: 415-420
- Developments of a water-maze procedure for studying spatial learning in the rat.J Neurosci Methods. 1984; 11: 47-60
- Brain reserve and the clinical expression of Alzheimer’s disease.Geriatrics. 1997; 52: S50-S53
- Exercise and brain neurotrophins.Nature. 1995; 373: 109
- Insulin-like growth factor I (IGF-I) protects cells from apoptosis by Alzheimer’s V642I mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner.J Neurosci. 2001; 21: 1902-1910
- Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year.Neuroscience. 1999; 94: 279-286
- Effects of environmental enrichment on cognitive function and hippocampal NGF in the nonhandled rats.Behav Brain Res. 1999; 103: 63-70
- Alzheimer’s disease: genetic studies and transgenic models.Annu Rev Genet. 1998; 32: 461-493
- Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus.Eur J Neurosci. 2004; 19: 234-246
- Alzheimer diseases: a model of gene mutations and susceptibility polymorphisms for complex psychiatric diseases.Am J Med Genet. 1998; 81: 49-57
- Primer3 on the WWW for general users and for biologist programmers.in: Krawetz S. Misener S. Bioinformatics Methods and Protocols: Methods in Molecular Biology. Humana Press, Totowa, NJ2000: 365-386 (source code available at http://fokker.wi.mit.edu/primer3)
- Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP.Neurobiol Aging. 2002; 23: 187-194
- The physiology of dominance in stable versus unstable social hierarchies.in: Mason W. Mendoza S. Primate social conflict. SUNY Press, New York1993: 171
- Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor.Brain Pathol. 2004; 14: 237-248
- The genetics and molecular pathology of Alzheimer’s disease: roles of amyloid and the presenilins.Neurol Clin. 2000; 18: 903-922
- Effects of stress on neurotrophic factor expression in the rat brain.Ann N Y Acad Sci. 1995; 771: 234-239
- Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life.JAMA. 1996; 275: 528-532
- Decreased release of the angiogenic peptide vascular endothelial growth factor in Alzheimer’s disease: recovering effect with insulin and DHEA sulfate.Dement Geriatr Cogn Disord. 2005; 19: 1-10
- What provides cerebral reserve?.Brain. 2004; 127: 1191-1199
- Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice.Glia. 2004; 46: 41-52
- Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.Proc Natl Acad Sci U S A. 1997; 94: 13287-13292
- Environmental conditions influence hippocampus-dependent behaviours and brain levels of amyloid precursor protein in rats.Eur J Neurosci. 2002; 16: 2405-2415
- Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus.Behav Brain Res. 1998; 93: 83-90
- Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus.J Neurosci. 2001; 21: 1628-1634
- Age-dependent cognitive decline in the APP23 model precedes amyloid deposition.Eur J Neurosci. 2003; 17: 388-396
- Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.Nat Neurosci. 1999; 2: 266-270
- Exercise enhances learning and hippocampal neurogenesis in aged mice.J Neurosci. 2005; 25: 8680-8685
- Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice.Neurobiol Dis. 2004; 14: 318-327
- Presenilin 1 familial Alzheimer’s disease mutation leads to defective associative learning and impaired adult neurogenesis.Neuroscience. 2004; 126: 305-312
- The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice.Exp Neurol. 2004; 188: 224-237
- Relatively brief environmental enrichment aids recovery of learning capacity and alters brain measures after postweaning brain lesions in rats.J Comp Physiol Psychol. 1977; 91: 33-50
- Participation in cognitively stimulating activities and risk of incident Alzheimer disease.JAMA. 2002; 287: 742-748
- Co-accumulation of vascular endothelial growth factor with beta-amyloid in the brain of patients with Alzheimer’s disease.Neurobiol Aging. 2004; 25: 283-290
- Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective.Nat Med. 1999; 5: 448-453
Article info
Publication history
Published online: June 28, 2006
Accepted:
April 12,
2006
Received in revised form:
December 8,
2005
Received:
May 27,
2005
Identification
Copyright
© 2006 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
