TABLE 1. Comparison of memory loss in aging rodents and APP rodents.
Shaded boxes indicate studies that directly compared phenotypes of transgenic mice and age-matched and older non-transgenic mice of the same background strain.
Similarities | Aged rats & mice | Citations | Transgenic APP mice and Aβ- infused rats |
Citations |
---|---|---|---|---|
Neurological deficits |
Neophobia in aged FVB/N mice |
Hsiao et al. (1995) Neuron. 15(5):1203–18. |
Neophobia in FVB/N mice with APP transgenes |
Hsiao et al. (1995) Neuron. 15(5):1203–18. |
Hypometabolism in specific brain regions |
Hypometabolism in brain regions linked to memory function in aged FVB/N mice |
Hsiao et al. (1995) Neuron. 15(5):1203–18. |
Hypometabolism in brain regions linked to memory function in FVB/N mice with APP transgenes |
Hsiao et al. (1995) Neuron. 15(5):1203–18. |
Deficits in LTP likely due to increased GABA inhibition |
Significantly greater enhancement of LTP by bicuculline in aged mice than in young adult mice |
Yoshiike et. al (2008) PLoS One. 3(8): e3029. |
Significantly greater enhancement of LTP by bicuculline in young adult APP/PS1 transgenic mice than in young adult non-transgenic mice |
Yoshiike et. al (2008) PLoS One. 3(8): e3029. |
In vivo LTP maintenance impaired |
Impaired maintenance, but not induction, of hippocampal LTP in aged rats |
Barnes et al. (1979) J Comp Physiol Psychol. 93(1): 74–104. |
Impaired maintenance, but not induction, of hippocampal LTP in transgenic mice (Tg2576, APP/PS1) and in Aβ-infused rats |
Chapman, et al. (1999) Nat Neurosci 2(3): 271–6 Gureviciene et al. (2004) Neurobiol Dis. 15(2): 188–95. Walsh et al. (2002) Nature 416(6880): 535–9. |
Hippocampal hyperexcitability |
Increased firing rates of CA3 place cells in aged rats |
Wilson et al. (2005) J Neurosci. 25(29):6877–86. |
Spontaneous seizure activity in hippocampal networks |
Palop et al. (2007) Neuron. 55(5):697–711. |
Impaired Ca2+ homeostasis in neurons |
Ca2+ elevated in neurons of aged rats; Ca2+ elevated in pre-synaptic terminals of aged rats; altered sources of Ca2+ influx during induction of LTP in aged rats; Ca2+ chelation restores LTP in slices from aged rats but reduces LTP in slices from young rats and reverses memory deficits in aged rats; |
Hajieva et al. (2009) Neurosci Lett. 451(2): 119–23. Tonkikh et al. (2006) Exp Neurol. 197(2): 291–300. Shankar et al. (1998) J Neurophysiol. 79(1): 334–41. Boric et al. (2008) J Neurosci. 28(32): 8034–9. Reviewed in Foster TC (2007) Aging Cell. 6(3): 319–25. |
No studies yet reported in pre-plaque APP transgenic mice that do not also contain a mutant PS1 transgene, which itself disrupts Ca2+ dynamics |
Reviewed in Green & LaFerla (2008) Neuron. 59(2): 190–4. Stutzman GE (2007) Neuroscientist. 13(5): 546–59. |
Hypothalamic- pituitary-adrenal (HPA) stress response defect |
Impaired HPA response to restraint- induced stress |
Bizon et al. (2001) Eur J Neurosci. 14(10): 1739–51 |
Aberrant HPA stress response to hypoglycemia in Tg2576 mice |
Pedersen et al. (1999) J Mol Neurosci. 13:(1–2): 159–65. |
Preservation of neuron number in hippocampus |
No neuronal loss in hippocampus of aged rats with spatial memory deficits |
Rapp & Gallagher (1996) Proc Natl Acad Sci U S A. 93(18): 9926– 30. |
No neuronal loss in hippocampus of memory-impaired Tg2576 mice or in aged PDAPP mice |
Irizarry et al. (1997) J Neuropathol Exp Neurol. 56(9): 965–73. Irizarry et al. (1997) J Neurosci. 17(18): 7053–9. |
Cholinergic system changes |
Shrinkage of basal forebrain neurons | Reviewed in Finch CE (1993) Trends Neurosci. 16(3): 104–10. |
Cholinergic terminal reorganization in Tg2576 × PS1 mice; basal forebrain neuron shrinkage in TgAPP mice with London mutation |
Wong et al. (1999) J Neurosci. 19(7): 2706–16. Bronfman et al. (2000) Neurobiol Dis. 7(3): 152–68. |
Oxidative stress markers increased |
Increased signatures of oxidative stress in aged rats with spatial memory deficits |
Nicolle et al. (2001) Neuroscience. 107(3): 415–31. |
Increased oxidative stress markers in aged Tg2576 mice |
Smith et al. (1998) J Neurochem. 70(5): 2212–5. Pappolla et al. (1999) J Pineal Res. 27(4): 226–9. Pratico et al. (2001) J Neurosci. 21(12): 4183–7 |
Caloric deprivation |
Caloric deprivation prevents memory loss in rats |
Pitsikas & Algeri (1992) Neurobiol Aging. 13(3): 369–73. |
Caloric restriction decreases amyloid deposition in APP and APP/PS1 mice; preserves spatial memory in Tg2576 mice |
Patel et al. (2005) Neurobiol Aging. 26(7): 995–1000. Mouton et al. (2009) Neurosci Lett. 464(3): 184–7. Qin et al. (2008) Ann N Y Acad Sci. 1147: 335–47. |
Beneficial effects of COX inhibition |
Nimesulide (COX-2 inhibitor) attenuates memory deficits in aged mice; NSAIDs (nimesulide, rofecoxib, naproxen) reverse memory deficits in aged mice, no effect in young mice |
Bishnoi et al. (2005) Methods Find Exp Clin Pharmacol. 27(7): 465–70. Jain et al. (2002) Behav Brain Res. 133(2): 369–76. |
NSAIDs prevent (ibuprofen) or reverse (ibuprofen, naproxen, MF- tricyclic) memory deficits in Tg2576 mice, no effect in non-tg |
Kotilinek et al. (2008) Brain. 131(Pt 3): 651–64. |
PKC-gamma elevation |
Increased in aged rats with spatial memory deficits |
Colombo et al. (1997) Proc Natl Acad Sci U S A. 94(25): 14195–9. Colombo & Gallagher (2002) Hippocampus. 12(2): 285–9. |
Increased in aged Tg2576 mice | Rossner et al. (2001) Eur J Neurosci. 13(2): 269–78. |
Environmental enrichment |
Environmental enrichment improves memory performance in aged but not young male mice; exercise improves memory in younger female mice, but exercise + cognitive enrichment needed to improve memory in older female mice |
Harburger et al. (2007) Behav Brain Res. 185(1): 43–8. Harburger et al. (2007) Behav Neurosci. 121(4): 679–88. |
Exercise, social interactions and cognitive enrichment improve cognitive function in APP and APP/PS1 transgenic mice, but also improve cognitive function in non- transgenic controls |
Costa et al. (2007) Neurobiol Aging 28: 831–844. Jankowsky et al. (2005) J Neurosci. 25(21):5217–5224. |
Brain Aβ elevation |
Murine Aβ rises with age in mice | Fukumoto et al. (2004) Am J Pathol. 164(2): 719–25. |
Human Aβ rises with age in APP transgenic mice |
Games et al. (1995) Nature. 373(6514): 523–7. Hsiao et al. (1996) Science. 274(5284): 99–102. Sturchler-Pierrat et al. (1997) Proc Natl Acad Sci U S A. 94(24): 13287–92. Chishti et al. (2001) J Biol Chem. 276(24): 21562–21570. |
Differences | Aged rats & mice | Citations |
Transgenic APP mice and Aβ- infused rats |
Citations |
Amyloid deposits | None (rodent Aβ) | Present (human Aβ) | ||
AMPA binding in hippocampus |
No change in aged rats; no relationship to memory |
Nicolle et al. (1996) Neuroscience. 74(3): 741–56. |
Increased in aged Tg2576 mice | Cha et al. (2001) Neurobiol Dis. 8(1): 90–102. |
NMDA binding in hippocampus |
Decreased in aged rats; inverse relationship to memory |
Nicolle et al. (1996) Neuroscience. 74(3): 741–56. Adams et al. (2001) J Comp Neurol. 432(2): 230–43. |
No change in aged Tg2576 mice | Cha et al. (2001) Neurobiol Dis. 8(1): 90–102. |
Effect of SOD2 overexpression |
SOD2 over expression has no effect on age-associated memory impairment or LTP |
Hu et al. (2007) Neurobiol Learn Mem. 87(3): 372–84. |
SOD2 over expression prevents memory impairments in Tg19959 mice |
Dumont et al. (2009) FASEB J. 23(8): 2459–66. |