Dataset Information

Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice.

ABSTRACT:

Introduction

The low-density lipoprotein receptor-related protein (LRP1) and its family members have been implicated in the pathogenesis of Alzheimer's disease. Multiple susceptibility factors converge to metabolic pathways that involve LRP1, including modulation of the processing of amyloid precursor protein (APP) and the clearance of A? peptide.

Methods

We used the Cre-lox system to lower LRP1 levels in hippocampal neurons of mice that develop Alzheimer-type amyloid by crosses between mice that express Cre recombinase under the transcriptional control of the GFAP promoter, mice that harbor loxp sites in the LRP1 gene, and the APPswe/PS1dE9 transgenic model. We compared amyloid plaque numbers in APPswe/PS1dE9 mice lacking LRP1 expression in hippocampus (n = 13) to mice with normal levels of LRP1 (n = 12). Student t-test was used to test whether there were significant differences in plaque numbers and amyloid levels between the groups. A regression model was used to fit two regression lines for these groups, and to compare the rates of A? accumulation.

Results

Immunohistochemical analyses demonstrated efficient elimination of LRP1 expression in the CA fields and dentate gyrus of the hippocampus. Within hippocampus, we observed no effect on the severity of amyloid deposition, the rate of A?40/42 accumulation, or the architecture of amyloid plaques when LRP1 levels were reduced.

Conclusions

Expression of LRP1 by neurons in proximity to senile amyloid plaques does not appear to play a major role in modulating the formation of these proximal deposits or in the appearance of the associated neuritic pathology.

SUBMITTER: Xu G

PROVIDER: S-EPMC4054673 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice.

Xu Guilian G Green Cameron C CC Fromholt Susan E SE Borchelt David R DR

Alzheimer's research & therapy 20120426 2

<h4>Introduction</h4>The low-density lipoprotein receptor-related protein (LRP1) and its family members have been implicated in the pathogenesis of Alzheimer's disease. Multiple susceptibility factors converge to metabolic pathways that involve LRP1, including modulation of the processing of amyloid precursor protein (APP) and the clearance of Aβ peptide.<h4>Methods</h4>We used the Cre-lox system to lower LRP1 levels in hippocampal neurons of mice that develop Alzheimer-type amyloid by crosses b ...[more]

PMID: 22537779

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Project description:OBJECTIVE The double transgenic mouse model (APPswe/PS1dE9) of Alzheimer's disease (AD) has been widely used in experimental studies. β-Amyloid (Aβ) peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. METHODS Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels of Aβ1-40, Aβ1-42 and 8-hydroxydeoxyguanosine (8-OHdG) in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. RESULTS The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ(1-40) and Aβ(1-42) were detected in these dead mice brains with a ratio of 1:10. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ(1-40) level in the blood was significantly higher than Aβ(1-42) level at the ages of 6 and 12 months (ratio 2.37:1). In contrast, the level of Aβ(1-42) in the brain (160.6 ng/mg protein) was higher than that of Aβ(1-40) (74 ng/mg protein) (ratio 2.17:1). In addition, the levels of Aβ(1-40) and Aβ(1-42) varied markedly among different brain regions. Aβ(1-42) level was significantly higher than Aβ(1-40) level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher γ-secretase activity but was more efficient in producing Aβ(1-42) peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. CONCLUSION These results suggest that this mouse model mimics the early-onset human AD and may represent full-blown disease at as early as 6-month age for experimental studies.

Project description:Systemic inflammation enhances the risk and progression of Alzheimer's disease (AD). Lipopolysaccharide (LPS), a potent pro-inflammatory endotoxin produced by the gut, is found in excess levels in AD where it associates with neurological hallmarks of pathology. Sex differences in susceptibility to inflammation and AD progression have been reported, but how this impacts on LPS responses remains under investigated. We previously reported in an APP/PS1 model of AD that systemic LPS administration rapidly altered hippocampal metabolism in males. Here, we used untargeted metabolomics to comprehensively identify hippocampal metabolic processes occurring at onset of systemic inflammation with LPS (100 µg/kg, i.v.) in APP/PS1 mice, at an early pathological stage, and investigated the sexual dimorphism in this response. Four hours after LPS administration, pathways regulating energy metabolism, immune and oxidative stress responses were simultaneously recruited in the hippocampi of 4.5-month-old mice with a more protective response in females despite their pro-inflammatory and pro-oxidant metabolic signature in the absence of immune stimulation. LPS induced comparable behavioural sickness responses in male and female wild-type and APP/PS1 mice and comparable activation of both the serotonin and nicotinamide pathways of tryptophan metabolism in their hippocampi. Elevations in N-methyl-2-pyridone-5-carboxamide, a major toxic metabolite of nicotinamide, correlated with behavioural sickness regardless of sex, as well as with the LPS-induced hypothermia seen in males. Males also exhibited a pro-inflammatory-like downregulation of pyruvate metabolism, exacerbated in APP/PS1 males, and methionine metabolism whereas females showed a greater cytokine response and anti-inflammatory-like downregulation of hippocampal methylglyoxal and methionine metabolism. Metabolic changes were not associated with morphological markers of immune cell activation suggesting that they constitute an early event in the development of LPS-induced neuroinflammation and AD exacerbation. These data suggest that the female hippocampus is more tolerant to acute systemic inflammation.

Dataset Information

Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice.

Introduction

Methods

Results

Conclusions

Publications

Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice.

Similar Datasets

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