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Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer’s disease mouse model.

ABSTRACT: Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer’s disease mouse model.

PROVIDER: PRJNA1215759 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32128122_1.fastq.gz	Fastqsanger.gz
	SRR32128122_2.fastq.gz	Fastqsanger.gz
	SRR32128123_1.fastq.gz	Fastqsanger.gz
	SRR32128123_2.fastq.gz	Fastqsanger.gz
	SRR32128124_1.fastq.gz	Fastqsanger.gz

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Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer’s disease mouse model.

Project description:Characteristic cerebral pathological changes of Alzheimer’s disease (AD) such as glucose hypometabolism or the accumulation of cleavage products of the amyloid precursor protein (APP), known as Aβ peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded protein response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in the UPR by targeting proteins for proteasomal degradation. We demonstrated previously that RHBLD4 cleaves APP in HEK293T cells, leading to decreased total APP and Aβ. More recently, we showed that RHBDL4 processes APP in mouse primary mixed cortical cultures as well. Here, we aim to examine the physiological relevance of RHBDL4 in the brain. We first found that brain samples from AD patients and an AD mouse model (APPtg) showed increased RHBDL4 mRNA and protein expression. To determine the effects of RHBDL4’s absence on APP physiology in vivo, we crossed APPtg mice to a RHBDL4 knockout (R4-/-) model. RHBDL4 deficiency in APPtg mice led to increased total cerebral APP and amyloidogenic processing when compared to APPtg controls. Contrary to expectations, as assessed by cognitive tests, RHBDL4 absence rescued cognition in 5-month-old female APPtg mice. Informed by unbiased RNAseq data, we demonstrated in vitro and in vivo that RHBDL4 absence leads to greater levels of active β-catenin due to decreased proteasomal clearance. Decreased β-catenin activity is known to underlie cognitive defects in APPtg mice and AD. Our work suggests that RHBDL4’s increased expression in AD, in addition to regulating APP levels, leads to aberrant degradation of β-catenin, contributing to cognitive impairment.

2025-01-29 | GSE288040 | GEO

miRNA sequencing of exosomes derived from N2A and APP-N2A cells

Project description:APP misexpression plays a crucial role in triggering a complex pathological cascade, leading to Alzheimer’s disease (AD). The aim of this study is for determine the influence of APP ectopic expression on the miRNA profiles of neuronal exosomes. In study, miRNA sequencing was done using the exosomes derived from N2A (control) and APP-N2A (N2A with APP overexpression).

2022-03-30 | E-MTAB-11106 | biostudies-arrayexpress

Differential and synergistic transcriptional effects of early amyloid-β and tau pathologies in the hippocampus of APP, Tau, and APP/Tau female mice

Project description:Alzheimer’s disease (AD) is characterized by memory loss associated with accumulation of amyloid-β (Aβ) and tau in the brain, but how memory-processing neural circuits are differentially affected by each pathology remains unclear. Here, we investigated the transcriptional vulnerability to single and concomitant Aβ and tau pathologies in 6-month-old transgenic mice expressing mutant human amyloid precursor protein (APP), Tau, or both (APP/Tau mice) in excitatory neurons. We identified differential and synergistic pathology-induced transcriptional responses in the hippocampus of AD transgenic mice. These findings support the idea that Aβ and tau pathologies exert synergistic effects to disrupt gene expression programs underlying vulnerability of memory neural circuits in AD.

2025-02-07 | GSE280199 | GEO

Gas6 improves plaque burden, yet worsens behavior and induces microglial inflammation in the APP/PS1 model of Alzheimer’s disease

Project description:We sought to determine the effects of Gas6 on Alzheimer’s disease pathology through overexpression of Gas6 using an adeno-associated viral vector in the APP/PS1 model of Alzheimer’s disease. 9 month old male and female APP/PS1 and nontransgenic littermates received bilateral stereotactic hippocampal injections of AAV-Gas6 or AAV-control, an attenuated Gas6 protein that does not bind the Axl receptor. One month after injections, mice performed a battery of behavioral tasks and brains were processed for immunohistochemistry, transcriptional analyses, and flow cytometry.

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APP levels mediate beta-amyloid but not tau-related aspects of Alzheimer’s disease in a Down syndrome model of cortical neurogenesis.

Project description:Early-onset Alzheimer’s disease-like pathology in Down syndrome (DS, trisomy 21) is commonly attributed to an increased dosage of the amyloid precursor protein (APP) gene. To test this central tenet of the amyloid-cascade hypothesis we deleted the supernumerary copy of the APP gene in trisomic DS iPSC, or upregulated APP expression in euploid human pluripotent stem cell lines with dCas9-VP64, and subjected these lines to prolonged cortical neural differentiation. Our data reveal that increased APP gene dosage and expression is necessary and sufficient for increased beta-amyloid production and pyroglutamate(E3)-containing plaque deposition, but is neither sufficient nor required for tau hyperphosphorylation, neurofibrillary tangle formation, or increased oxidative stress-induced apoptosis in neurons. Transcriptome comparisons of the isogenic neurons demonstrates that the supernumerary APP gene copy has profound temporally-modulated genome-wide effects on gene expression during differentiation and maturation of DS neuronal cultures that link APP function to regulation of genes involved in neuronal synaptic function and outgrowth of neuronal processes. Collectively, our data reveal that APP plays an important role in the amyloidogenic aspects of Alzheimer’s disease, but challenge the hypothesis that increased APP levels are solely responsible for hyperphosphorylation of tau or enhanced oxidative stress-induced neuronal cell death in Down syndrome associated AD-pathogenesis.

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Staging Alzheimer’s disease in brains and retinas of APP/PSEN1 mice by transcriptional profiling

Project description:Alzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age).

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Alzheimer’s Disease-Related Mutations in APP Influence Colorectal Tumor Formation in a Sex-Dependent Manner

Project description:Cancer and Alzheimer’s disease (AD) are major age-associated diseases. Numerous studies have indicated common mechanisms and biological interactions between these conditions. Furthermore, epidemiological data demonstrate negative correlations between several cancers and AD. Despite this, few studies have explored their mutual influence on pathological outcomes. In this study, we utilized a human APP mutant knock-in AD mouse model to investigate how familial mutations influence colorectal cancer development. Using a colitis-associated colorectal cancer model, APP mutations promoted colon tumor formation in male mice but inhibited it in female mice. Correspondingly, inflammatory changes were reduced in the colons of female mice. Transcriptome analysis revealed differential expression, particularly in the enrichment of neuronal marker, steroid hormone, and immune cell signaling pathways. Additionally, distinct macrophage subtypes and neuronal profiles were observed in the colons of male and female APP mutant mice. These findings provide the first elucidation of the sex-dependent effects of APP mutations on colon cancer formation.

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