Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer's disease

ABSTRACT: Alzheimerâs disease (AD) is a neurodegenerative disease characterized by a marked decline in cognition and memory formation. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, namely the ones that are produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (AÎ²) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways that are relevant for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive AÎ² accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12 months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3 months, which became lower than WT at 5-6 and 11-12 months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3 months. Altogether, these findings provide new insights on a possible interplay between type I and type II IFN responses in AD and point to IFNs as mediators of cognitive decline in aging and in AD. The CP transcriptome of at least 3 mice of each age (3, 5-6 and 11-12 months) and of each genotype (WT or J20) was analyzed and compared.

ORGANISM(S): Mus musculus

SUBMITTER: Giovanni Coppola

PROVIDER: E-GEOD-66598 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

Project description:Alzheimer’s disease (AD) is a major neurodegenerative disease characterized by extracellular amyloid β (Aβ) plaques and intracellular hyperphosphorylated tau (P-tau). Increasing evidence indicates that extracellular vesicles (EVs) play an important role in AD pathogenesis. We previously reported that the choroid plexus epithelial (CPE) cells, present at the interface between blood and cerebrospinal fluid (CSF), show increased secretion of EVs into the CSF in response to peripheral inflammation. Here, we studied the importance of CP-derived EVs in AD pathogenesis. We observed increased EV levels in the CSF of 7 weeks old transgenic APP/PS1 mice, correlating with higher Aβ CSF levels at this age, while levels normalized with age. To study whether the elevated Aβ CSF levels might be responsible for this increase, mice were intracerebroventricularly (icv) injected with Aβ oligomers (AβO) which revealed a significant increase in the amount of CD9 and CD81 positive EVs in the CSF. The importance of the CPE cells as EV source was shown by in vitro analysis of AβO stimulated primary CPE cells and in vivo analysis of the CP by transmission electron microscopy (TEM). Evaluation of EV marker immunostaining, both from AβO icv injected mice and APP/PS1 mice, confirmed the upregulation of EV biogenesis in the CP. Interestingly, AβO-induced, CP-derived EVs induced pro-inflammatory effects in mixed cortical cultures (MCC) whereas proteome analysis revealed the presence of complement protein C3, amongst other inflammatory proteins. Additionally, we could show for the first time that AβO induce an upregulation of C3 in CPE cells. These data highlight the CP and CP-derived, C3-containing EVs as novel players in the emerging importance of the complement pathway in the pathogenesis of AD. Strikingly, inhibition of EV production using GW4869 resulted in protection against the AβO-induced cognitive decline. In conclusion, our results show that intraventricular AβO induce both C3 activation and EV secretion by the CP and that these EVs contain pro-inflammatory molecules, including C3, which play a role in neuroinflammation and loss of cognition. This suggests that inhibition of EV production by the CP might be an interesting therapeutic approach to be explored in the prevention or treatment of AD.

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The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer's disease

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