Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains

Janus, Christopher; Flores, Abigail Y.; Xu, Guilian; Borchelt, David R.

doi:10.1016/j.neurobiolaging.2015.05.010

Cited by 78 publications

(77 citation statements)

References 76 publications

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“…Procedural learning is typically spared in mild AD (17), and the procedural demands of the assay appear to be minimal in humans. In contrast, hAPP mice had significant deficits (Table 1 and Figure 1E), as reported in this (18) and other transgenic lines (19,20). The procedural demands of the mouse assay are substantial: mice must overcome their tendency to swim along the wall and instead learn to climb onto a platform to escape the water.…”

Section: Resultssupporting

confidence: 55%

Cross-species translation of the Morris maze for Alzheimer’s disease

Possin¹,

Sanchez²,

Anderson-Bergman³

et al. 2016

Journal of Clinical Investigation

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Section: Resultssupporting

confidence: 55%

Cross-species translation of the Morris maze for Alzheimer’s disease

Possin¹,

Sanchez²,

Anderson-Bergman³

et al. 2016

Journal of Clinical Investigation

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“…Body weights were analyzed using two-way repeated-measures ANOVA with Holm-Sidak's multiple comparisons test. For NOR and Y-maze, a composite z-score was used to determine treatment effect on overall memory deficits [17]. For this, individual mouse values (recognition index and % entries in novel arm) were normalized to a z-score using the mean and standard deviation of the WT group.…”

Section: Discussionmentioning

confidence: 99%

Hematologic safety of chronic brain‐penetrating erythropoietin dosing in APP/PS1 mice

Sun

Yang

Whitman

et al. 2019

A&D Transl Res & Clin Interv

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Introduction Low blood‐brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor‐mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB‐penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb‐EPO dosing, in comparison to recombinant human EPO (rhu‐EPO), in AD mice. Methods Male APPswe PSEN1dE9 (APP/PS1) mice (9.5 months) were treated with saline (n = 11), and equimolar doses of cTfRMAb‐EPO (3 mg/kg, n = 7), or rhu‐EPO (0.6 mg/kg, n = 9) 2 days/week subcutaneously for 6 weeks, compared to saline‐treated wild‐type mice (n = 10). At 6 weeks, exploration and memory were assessed, and mice were sacrificed at 8 weeks. Spleens were weighed, and brains were evaluated for amyloid beta (Aβ) load and synaptophysin. Blood was collected at 4, 6 and 8 weeks for a complete blood count and white blood cells differential. Results cTfRMAb‐EPO transiently increased reticulocyte counts after 4 weeks, followed by normalization of reticulocytes at 6 and 8 weeks. rhu‐EPO transiently increased red blood cell count, hemoglobin and hematocrit, and significantly decreased mean corpuscular volume and reticulocytes at 4 weeks, which remained low at 6 weeks. At 8 weeks, a significant decline in red blood cell indices was observed with rhu‐EPO treatment. Exploration and cognitive deficits were significantly worse in APP/PS1‐rhu‐EPO mice. Both cTfRMAb‐EPO and rhu‐EPO decreased 6E10‐positive brain Aβ load; however, cTfRMAb‐EPO and not rhu‐EPO selectively reduced brain Aβ1‐42 and elevated synaptophysin expression. Discussion Chronic treatment with cTfRMAb‐EPO results in better hematologic safety, behavioral, and therapeutic indices compared with rhu‐EPO, supporting the development of this BBB‐penetrable EPO analog for AD.

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“…An earlier study reported that diffuse amyloid plaques begin to appear in the hippocampus and cerebral cortex of APP/PS1 mice at 3 months old (Trinchese et al 2004). Subsequent studies have revealed an age-dependent pattern of Aβ burden in this AD model (Samaroo et al 2012;Janus et al 2015). By use of thioflavin-S and 6E10 immunostaining, we found that 24-month-old APP/PS1 mice versus their 20-month counterparts have a higher percentage of area occupied by thioflavin-Slabeled core plaques (7.24 vs. 3.15 %) or 6E10-labeled diffusing plaques (3.02 vs. 3.65 %) in the hippocampus .…”

Section: Discussionmentioning

confidence: 89%

“…APP/PS1 transgenic mice expressing mutant human APP and PS1 genes are a useful research tool to study Aβ-related pathogenesis. There are several studies characterizing cognitive as well as noncognitive abnormality in APP/PS1 mice at 15-24 months of age (Morgan et al 2000;Arendash et al 2001;Sadowski et al 2004;Wilcock et al 2004;Hooijmans et al 2007;Minkeviciene et al 2008;Pistell et al 2008;Mei et al 2010;Ke et al 2011;Gengler et al 2012;Manczak and Reddy 2012;Wang et al 2012;Duffy and Hölscher 2013;Do et al 2014;Huang et al 2015;Janus et al 2015;Sahlholm et al 2015;Yousefi et al 2015) (A detailed summary is available in Table 2). However, the majority of experiments utilize young or adult APP/PS1 mice, which does not replicate typical hallmarks of AD, such as severe hippocampal atrophy and extensive neuronal loss (Bales 2012;Bilkei-Gorzo 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Correspondingly, various transgenic rodent models, such as those overexpressing mutant human APP or with both PS1 and tau, have been developed, providing valuable insights into specific aspects of AD pathogenesis (Bales 2012;Braidy et al 2012;Bilkei-Gorzo 2014;Webster et al 2014). Among these, APP/PS1 double transgenic mice are an extensively used model, showing progressive age-related development of Aβ accumulation and cognitive deficits (Jankowsky et al 2001;Trinchese et al 2004;van Groen et al 2006;Meyer-Luehmann et al 2009;Filali et al 2011;Janus et al 2015). Furthermore, previous studies have revealed positive results, such as demonstrating various antioxidants (Garcia-Alloza et al 2010;Varamini et al 2014;Yanagisawa et al 2015), neuroprotective agents (Kilgore et al 2010;Peng et al 2012;Li et al 2014), anti-neuroinflammation (Cherry et al 2015;Guo et al 2015), immune therapy (Sudduth et al 2013;Carrera et al 2013;Zhang et al 2015), and nonpharmacological interventions (Liu et al 2011;Jankowsky et al 2005), which can attenuate or even reserve AD-like pathology in APP/PS1 mice.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains

Cited by 78 publications

References 76 publications

Cross-species translation of the Morris maze for Alzheimer’s disease

Cross-species translation of the Morris maze for Alzheimer’s disease

Hematologic safety of chronic brain‐penetrating erythropoietin dosing in APP/PS1 mice

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

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