Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease

Brown, Richard E.

doi:10.1016/j.bbr.2009.01.039

Cited by 111 publications

(76 citation statements)

References 29 publications

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“…Previous studies report that APP/PS1 mice show reference memory impairments by 3 months of age and persist throughout life (Reiserer et al 2007;Bernardo et al 2009;O'Leary and Brown 2009). By comparing these results with our previous Y-maze test for behavioral analysis of 11-12-month-old APP/PS1 mice , we found that 24-month-old APP/PS1 cohorts show more severe working and reference memory impairment.…”

Section: Discussionsupporting

confidence: 60%

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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Section: Discussionsupporting

confidence: 60%

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

Huang

Nie

Cao

et al. 2016

AGE

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“…Insulinlike growth factor I (IGF-I), through its cognate receptor IGF-1R and downstream effectors, controls stress resistance, aging, and lifespan . Since aging is modulated by insulin-like signals in the brain (Taguchi et al, 2007;Kappeler et al, 2008;, this pathway could function as a molecular bridge between physiological aging and AD pathogenesis (Carro et al, 2002). In accord with that, constitutive heterozygous knock-out of IGF-1R in an APP/PS1 AD mouse model reduces astrogliosis, prevents neuronal death, and alleviates ADassociated cognitive deficits (Cohen et al, 2009).…”

Section: Introductionmentioning

confidence: 73%

“…APPswe/PS1dE9 transgenic mice (Jankowsky et al, 2004) were obtained from Jackson Laboratory (stock 5864), and CaMKCre-ER T2 transgenic mice (Erdmann et al, 2007) were obtained from European Mutant Mouse Archives (EMMA 02125). APPswe/PS1dE9 and CaMKCreER T2 transgenes were backcrossed to IGF-1R flox/flox knock-in mice (Kappeler et al, 2008) were used as non-AD controls (abbreviated WT). Mice were maintained in a specific pathogen free barrier facility using individually ventilated cages (Tecniplast).…”

Section: Methodsmentioning

confidence: 99%

Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance

et al. 2015

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Alzheimer's disease (AD) is a frequent and irreversible age-related neurodegeneration without efficient treatment. Experimental AD in mice responds positively to decreased insulin-like growth factor I (IGF-I) signaling, a pathway also implicated in aging. Here we aimed to protect the aging brain from devastating amyloid pathology by making specifically adult neurons resistant to IGF signaling. To achieve that, we knocked out neuronal IGF-1R during adulthood in APP/PS1 mice. We found that mutants exhibited improved spatial memory and reduced anxiety. Mutant brains displayed fewer amyloid plaques, less amyloid-␤ (A␤), and diminished neuroinflammation. Surprisingly, adult neurons undergoing IGF-1R knock-out reduced their apical soma and developed leaner dendrites, indicative of remarkable structural plasticity entailing condensed forebrain neuroarchitecture. Neurons lacking IGF-1R in AD showed less accumulation of A␤-containing autophagic vacuoles. At the same time, plasma A␤ levels were increased. Our data indicate that neuronal IGF-1R ablation, via preserved autophagic compartment and enhanced systemic elimination, offers lifelong protection from AD pathology by clearing toxic A␤. Neuronal IGF-1R, and possibly other cell size-controlling pathways are promising targets for AD treatment.

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“…The cognitive function of APPswe/PS1dE9 mice was tested 1 y post-BM transplantation with the Barnes maze, using the established protocol (19,32). The test involved 5 d of acquisition training with two trials per day.…”

Section: Barnes Maze Testmentioning

confidence: 99%

TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation

Liu

Hao

et al. 2012

The Journal of Immunology

344

239

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Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer’s disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741–744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer’s amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer’s disease pathogenesis.

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Visuo-spatial learning and memory deficits on the Barnes maze in the 16-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease

Cited by 111 publications

References 29 publications

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

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

Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance

TLR2 Is a Primary Receptor for Alzheimer’s Amyloid β Peptide To Trigger Neuroinflammatory Activation

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