Suppression of Wnt/β-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer’s Disease

Macyczko, Jesse R.; Wang, Na; Zhao, Jing; Ren, Yingxue; Lü, Wenyan; Ikezu, Tadafumi C.; Zhao, Na; Liu, Chia-Chen; Bu, Guojun; Li, Yonghe

doi:10.1007/s12035-022-03065-1

Cited by 7 publications

(4 citation statements)

References 71 publications

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“…Mouse cortex samples were homogenized in Trizol (Life Technologies, Carlsbad, CA, USA) and RNA was extracted as previously described [23]. Mouse sFRP1 real-time primer set (PPM04438C-200) and mouse GAPDH real-time primer set (PPM02946E-200) were purchased from Qiagen.…”

Section: Quantitative Real-time Pcr Of Sfrp1mentioning

confidence: 99%

“…The TBS-T insoluble pellets were re-suspended in 70% formic acid (FA). The preparation of the TBS-T and FA soluble fractions were described before [23,24].…”

Section: Preparation Of Mouse Brain Tbs-t and Fa Fractionsmentioning

confidence: 99%

“…Western blot analyses were conducted under reducing conditions as described before [23]. Specially, 16 μg protein of each TBS-T fraction and 1.2 μg protein of each FA fraction were loaded per well.…”

Section: Western Blottingmentioning

confidence: 99%

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Upregulation of sFRP1 Is More Profound in Female than Male 5xFAD Mice and Positively Associated with Amyloid Pathology

Macyczko

Wang

Lü

et al. 2023

JAD

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The prevalence of Alzheimer’s disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice. Importantly, female 5xFAD mice accumulated more Aβ than males, and sFRP1 protein levels were positively associated with Aβ42 levels in 5xFAD mice. Our study suggests that sFRP1 is associated with amyloid pathology in a sex-dependent manner.

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Section: Quantitative Real-time Pcr Of Sfrp1mentioning

confidence: 99%

“…The TBS-T insoluble pellets were re-suspended in 70% formic acid (FA). The preparation of the TBS-T and FA soluble fractions were described before [23,24].…”

Section: Preparation Of Mouse Brain Tbs-t and Fa Fractionsmentioning

confidence: 99%

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Upregulation of sFRP1 Is More Profound in Female than Male 5xFAD Mice and Positively Associated with Amyloid Pathology

Macyczko

Wang

Lü

et al. 2023

JAD

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“…Consistently, studies in mouse models have found that both Apoe deficiency and human APOE4 isoform impair the hippocampal neurogenesis [ 57 , 58 ]. Of note, our group recently described a downregulation of Wnt/β-catenin pathway in human iPSC‑derived astrocytes carrying APOE4 compared to those carrying APOE3 [ 66 ], which is opposite to the effects of APOE deficiency. The discrepancy in the effects of APOE4 and APOE deficiency on brain cell differentiation requires further investigation in future.…”

Section: Discussionmentioning

confidence: 99%

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids

Zhao,

Ikezu,

et al. 2023

Stem Cell Res Ther

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Background The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. Methods We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE−/−) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE−/− cerebral organoids at Day 90. Results We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/β-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 (SFRP1) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. Conclusions Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

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Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases

Faraji,

Ebadpour,

Abavisani

et al. 2024

Mol Neurobiol

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Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer’s disease and Parkinson’s disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.

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Suppression of Wnt/β-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer’s Disease

Cited by 7 publications

References 71 publications

Upregulation of sFRP1 Is More Profound in Female than Male 5xFAD Mice and Positively Associated with Amyloid Pathology

Upregulation of sFRP1 Is More Profound in Female than Male 5xFAD Mice and Positively Associated with Amyloid Pathology

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids

Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases

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