Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: Relationships to β-amyloid deposition and neurotransmitter abnormalities

Savonenko, Alena; Xu, Guilian; Melnikova, Tatiana; Morton, Johanna L.; Gonzales, Victoria; Wong, Molly; Price, Donald L.; Tang, Florence; Markowska, Alicja L.; Borchelt, David R.

doi:10.1016/j.nbd.2004.10.022

Cited by 353 publications

(314 citation statements)

References 62 publications

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“…We have also reported a significant degeneration in noradrenergic neurons in the LC in dtg APP/PS1 mice at 15 months of age (O'Neil et al in press). Another study in the same line of dtg APP/PS1 mice (Savenenko et al 2005), which found no differences in cognitive performance at 6-or 18-months of age, have reported mild decreases in acetylcholinesterase histochemical staining and somatostatin levels in cortex at 18 months of age. Szapacs et al (2004) reported reduced 5-HT levels in hippocampus at 18 months of age and reduced NE levels at 12-and 18-months of age.…”

Section: Discussionmentioning

confidence: 85%

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

Manaye

Wang

O’Neil

et al. 2007

AGE

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Murine models that mimic the neuropathology of Alzheimer's disease (AD) have the potential to provide insight into the pathogenesis of the disease and lead to new strategies for the therapeutic management of afflicted patients. We used magnetic resonance imaging (MRI), design-based stereology, and high performance liquid chromatography (HPLC) to assess the age-related neuropathology in double transgenic mice that overexpress two AD-related proteins-amyloid precursor protein (APP) and presenilin 1 (PS1)-and age-and gender-matched wild-type (WT) controls. In mice ranging in age from 4-28 months, total volumes of the hippocampal formation (V HF ) and whole brain (V brain ) were quantified by the Cavalieri-point counting method on a systematic-random sample of coronal T2-weighted MRI images; the same stereological methods were used to quantify V HF and V brain after perfusion and histological processing. To assess changes in ADtype beta-amyloid (Aβ) plaques, sections from the hippocampal formation and amylgdaloid complex of mice aged 5, 12, and 15 months were stained by Congo Red histochemistry. In aged mice with large numbers of amyloid plaques, systematic-random samples of sections were stained by GFAP immunocytochemistry to assess gender and genotype effects on total numbers of astrocytes. In addition, levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-HT metabolites were assayed by HPLC in fresh-frozen samples from neocortex, striatum, hippocampus, and brainstem. We confirmed age-related increases in amyloid plaques, beginning with a few plaques at 5 months of age and increasing densities by AGE (2007) 12 and 15 months. At 15 months of age, there were robust genotype effects, but no gender effects, on GFAP-immunopositive astrocytes in the amygdaloid complex and hippocampus. There were no effects on monoamine levels in all brain regions examined, and no volume changes in hippocampal formation or whole brain as quantified on either neuroimages or tissue sections. Strong correlations were present between volume estimates from MRI images and histological sections, with about 85% reduction in mean V HF or mean V brain between MRI and processed histological sections. In summary, these findings show that the double transgenic expression of AD-type mutations is associated with age-related increases in amyloid plaques and astrocytosis; however, this model does not recapitulate the cortical atrophy or neurochemical changes that are characteristic of AD.29:87-96 DOI 10.1007/s11357-007-9035-

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Section: Discussionmentioning

confidence: 85%

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

Manaye

Wang

O’Neil

et al. 2007

AGE

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“…In contrast, by the time five separate spatial locations had been trained in a single context, the mice would have been in a position where their memory retrieval mechanism would need to successfully distinguish between five separate long-term memory traces and somehow identify which was the appropriate memory to recall that day-a process that would entail contextual pattern separation. This appears to be a difficulty for PDAPP mice (Savonenko et al 2005), with episodic-like tasks (such as serial reversal) being particularly sensitive for revealing such a deficit (Morris 2001). The process of encoding highly similar but distinct episodes as separate memory traces is thought to require neural activity and plasticity in the dentate gyrus (DG).…”

Section: Discussionmentioning

confidence: 99%

Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?

Daumas¹,

Sandin²,

Chen³

et al. 2008

Learn. Mem.

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Two experiments were conducted to investigate the possibility of faster forgetting by PDAPP mice (a well-established model of Alzheimer’s disease as reported by Games and colleagues in an earlier paper). Experiment 1, using mice aged 13–16 mo, confirmed the presence of a deficit in a spatial reference memory task in the water maze by hemizygous PDAPP mice relative to littermate controls. However, after overtraining to a criterion of equivalent navigational performance, a series of memory retention tests revealed faster forgetting in the PDAPP group. Very limited retraining was sufficient to reinstate good memory in both groups, indicating that their faster forgetting may be due to retrieval failure rather than trace decay. In Experiment 2, 6-mo-old PDAPP and controls were required to learn each of a series of spatial locations to criterion with their memory assessed 10 min after learning each location. No memory deficit was apparent in the PDAPP mice initially, but a deficit built up through the series of locations suggestive of increased sensitivity to interference. Faster forgetting and increased interference may each reflect a difficulty in accessing memory traces. This interpretation of one aspect of the cognitive deficit in human mutant APP mice has parallels to deficits observed in patients with Alzheimer’s disease, further supporting the validity of transgenic models of the disease.

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“…First, SST-NPY containing interneurons have been implicated in learning and memory [93][94][95][96] and post-mortem brain studies of AD repeatedly observed a severe loss of SST immunoreactive neurons and axons. 31,95,[97][98][99][100] In addition, APPswe/PS1dE9 amyloid plaque producing mice show reduced SST levels in the cortex, 101 and this is likely mediated through the interference of amyloid-beta (Ab) with the BDNF-induced activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K)/Akt pathways. 102 In contrast, it appears that inducing increased expression of SST may be beneficial for patients suffering from AD: compounds increasing SST expression are in phase II clinical trials as cognition enhancing agents (FK962, Astellas Pharma, Tokyo, Japan), 103 and transgenic models of amyloid deposition are reversed by environmental enrichment, 25 which is known to induce SST-NPY expression via a BDNF-dependent pathway.…”

Section: Discussionmentioning

confidence: 99%

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

et al. 2006

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Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: Relationships to β-amyloid deposition and neurotransmitter abnormalities

Cited by 353 publications

References 62 publications

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: Deficit in memory retrieval associated with increased sensitivity to interference?

Specificity and timing of neocortical transcriptome changes in response to BDNF gene ablation during embryogenesis or adulthood

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