Brain-targeting liposome-based APOE2 gene delivery exacerbates soluble amyloid-β accumulation in AppNL-G-F mice
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PROVIDER: PRJNA1173096 | ENA |
REPOSITORIES: ENA
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Project description:Alzheimer’s disease (AD) is the most common cause of late-life dementia characterized by progressive neurodegeneration and brain deposition of amyloid-β (Aβ) and phosphorylated tau. The APOE ε2 encoding apolipoprotein E (APOE2) is a protective allele against AD among the three genotypes (APOE ε2, ε3, ε4), while APOE4 is the strongest genetic factor substantially increasing AD risk. APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where APOE2 has a superior function compared to APOE3 and APOE4. Gene therapy that increases APOE2 levels in the brain is, therefore, a promising therapeutic strategy for AD treatment. We previously reported that PEGylated liposomes conjugated with transferrin and a cell-penetrating peptide Penetratin sufficiently deliver chitosan-APOE2 cDNA plasmid complex into the brain of wild-type mice. Here, we investigated how brain-targeting liposome-based APOE2 gene delivery influences Aβ)-related pathologies in amyloid model AppNL-G-F knockin mice at 12-month-old. We found a trend of reductions of insoluble Aβ levels in the mouse cortices 1 month after APOE2 gene therapy. Furthermore, in the AppNL-G-F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA-sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin. Together, our results suggest that brain-targeting liposome-based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.
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Project description:Genetic variation in the APOE gene modulates melanoma progression. To identify tumor cell-intrinsic mechanisms underlying differences in tumor progression between APOE2 and APOE4 genotypes, we crossed the Braf/Pten/Cre (BPC) genetically engineered mouse model with APOE2 (BPCE2) and APOE4 (BPCE4) knock-in mice. We performed RNA-Seq on tumors derived from these mice. This analysis revealed protein synthesis as a process that is enhanced by APOE2. **Note: Raw fastq sequencing files for these samples were irrevocably corrupted due to a server failure and therefore could not be provided. Kallisto transcript abundance estimates have been included as processed data.**
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Project description:ObjectiveRecent evidence supports a link between increased TDP-43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP-43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP-43 pathology and related neurodegeneration in the absence of typical AD pathologies.MethodsWe overexpressed human TDP-43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe-knockout (Apoe-KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP-43 overexpression-related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP-43 pathology in 160 postmortem brains from autopsy-confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) in the Mayo Clinic Brain Bank.ResultsWe found that TDP-43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe-KO mice. In the motor cortex of the ALS and FTLD-MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP-43-positive dystrophic neurites.InterpretationOur data suggest a genotype-specific effect of APOE on TDP-43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830-843.
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Project description:The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer’s disease risk: the APOE4 allele increases risk while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in humans and mice. We hypothesized that the protective effects of APOE2 are mediated through the endosomal pathway during aging. In contrast to Alzheimer’s disease and APOE4 models, we detected normal morphology and abundance of early endosomes within cortical neurons of APOE2 targeted-replacement mice during aging despite decreased rab5b recruitment to early endosomes. Similarly, the morphology and abundance of retromer-associated vesicles was normal in APOE2 mice, despite reduced recruitment of vesicle-associated VPS35. Significantly, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, indicative of an enhanced endosomal cargo clearance to the extracellular space that contributes to a homeostatic balance of endosomal functions. Our findings thus demonstrate that APOE2 effectively offsets endosomal pathway changes during aging to preserve its integrity by enhancing exosome biogenesis, mitigating age-driven endosomal dysfunction that contributes to Alzheimer’s disease risk.
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Project description:Plasma membrane repair is a rapid cellular response for resealing of membrane for cell survival. In the early step of repair process, TRIM72 is known to a key initiator for facilitating patch membrane to the damaged membrane site. When acute membrane injury happens, TRIM72 is also known to sensitively generate disulfide bonds formations by reactive oxygen species and further oligomerize with each other. We tried to clarify this repair system using in vitro reconstruction of TRIM72-liposome complex and find critical sites using cross-linker mass spectrometry. Using each four different length of sulfhydryl reactive cross-linkers, TRIM72 cross-linked with each other on the negatively charged liposome surface only. We also identified that the cross-linking bridges were highly conserved except bismaleimidoethane as a shortest arm length about 8 Å only. Our results indicated that the B2-box/B2-box locates closely with each other on the liposome surface. Furthermore, freely open RING domain is rearranged into the specific conformation, where located near the H2 helix of coiled coil domain. It suggests that the conformational changes of TRIM72 are induced by higher order assembly on the negative charged membrane surface.
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Project description:A hallmark of Alzheimer Disease is the accumulation of aggregation-prone amyloid beta peptides, which can assemble into smaller aggregates and deposit in the form of amyloid plaques. Here we used the recently introduced APPNL-F mouse model of Alzheimer Disease, which faithfully recapitulates the amyloid beta pathology of the disease, to identify early changes to the global proteome. Using a workflow that interrogated the brain proteome of these mice by quantitative mass spectrometry at five, ten and fifteen months of age.
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