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.