Dataset Information

SPIN90 Deficiency Ameliorates Amyloid β Accumulation by Regulating APP Trafficking in AD Model Mice.

ABSTRACT: Alzheimer's disease (AD), a common form of dementia, is caused in part by the aggregation and accumulation in the brain of amyloid β (Aβ), a product of the proteolytic cleavage of amyloid precursor protein (APP) in endosomes. Trafficking of APP, such as surface-intracellular recycling, is an early critical step required for Aβ generation. Less is known, however, about the molecular mechanism regulating APP trafficking. This study investigated the mechanism by which SPIN90, along with Rab11, modulates APP trafficking, Aβ motility and accumulation, and synaptic functionality. Brain Aβ deposition was lower in the progeny of 5xFAD-SPIN90KO mice than in 5xFAD-SPIN90WT mice. Analysis of APP distribution and trafficking showed that the surface fraction of APP was locally distinct in axons and dendrites, with these distributions differing significantly in 5xFAD-SPIN90WT and 5xFAD-SPIN90KO mice, and that neural activity-driven APP trafficking to the surface and intracellular recycling were more actively mobilized in 5xFAD-SPIN90KO neurons. In addition, SPIN90 was found to be cotrafficked with APP via axons, with ablation of SPIN90 reducing the intracellular accumulation of APP in axons. Finally, synaptic transmission was restored over time in 5xFAD-SPIN90KO but not in 5xFAD-SPIN90WT neurons, suggesting SPIN90 is implicated in Aβ production through the regulation of APP trafficking.

SUBMITTER: Oh Y

PROVIDER: S-EPMC9504172 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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SPIN90 Deficiency Ameliorates Amyloid β Accumulation by Regulating APP Trafficking in AD Model Mice.

Oh Youngsoo Y Lee Wongyoung W Kim So Hee SH Lee Sooji S Kim Byeong C BC Lee Kun Ho KH Kim Sung Hyun SH Song Woo Keun WK

International journal of molecular sciences 20220912 18

Alzheimer's disease (AD), a common form of dementia, is caused in part by the aggregation and accumulation in the brain of amyloid β (Aβ), a product of the proteolytic cleavage of amyloid precursor protein (APP) in endosomes. Trafficking of APP, such as surface-intracellular recycling, is an early critical step required for Aβ generation. Less is known, however, about the molecular mechanism regulating APP trafficking. This study investigated the mechanism by which SPIN90, along with Rab11, modu ...[more]

PMID: 36142484

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Project description:The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also via endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin-severing protein, in actin dynamics and pathogen-triggered endocytic processes. Moreover, the binding of Aβ42 oligomers to β1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface β1-integrin. However, a role for cofilin in APP processing and Aβ metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Aβ production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aβ deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin+/-). However, the reduction of Aβ load in APP/PS1;cofilin+/- mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Aβ deposits. Primary microglia isolated from cofilin+/- mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aβ42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Aβ accumulation via dual and opposing endocytic mechanisms of promoting Aβ production in neurons and inhibiting Aβ clearance in microglia.-Liu, T., Woo, J.-A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid-β clearance.

Project description:Clinical evidence shows that postmenpausal women are almost twice as likely to develop Alzheimer's disease (AD) as men of the same age, and estrogen is closely related to the occurrence of AD. Estrogen receptor (ER) α is mainly expressed in the mammary gland and other reproductive organs like uterus while ERβ is largely distributed in the hippocampus and cardiovascular system, suggesting that ERβ selective agonist is a valuable drug against neurodegenerative diseases with low tendency in inducing cancers of breast and other reproductive organs. In this study we identified a natural product patchouli alcohol (PTA) as a selective ERβ agonist which improved the cognitive defects in female APP/PS1 mice, and explore the underlying mechanisms. Six-month-old female APP/PS1 mice were administered PTA (20, 40 mg · kg-1 · d-1, i.g.) for 90 days. We first demonstrated that PTA bound to ERβ with a dissociation constant (KD) of 288.9 ± 35.14 nM in microscale thermophoresis. Then we showed that PTA administration dose-dependently ameliorated cognitive defects evaluated in Morris water maze and Y-maze testes. Furthermore, PTA administration reduced amyloid plaque deposition in the hippocampus by promoting microglial phagocytosis; PTA administration improved synaptic integrity through enhancing BDNF/TrkB/CREB signaling, ameliorated oxidative stress by Catalase level, and regulated Bcl-2 family proteins in the hippocampus. The therapeutic effects of PTA were also observed in vitro: PTA (5, 10, 20 μM) dose-dependently increased phagocytosis of o-FAM-Aβ42 in primary microglia and BV2 cells through enhancing ERβ/TLR4 signaling; PTA treatment ameliorated o-Aβ25-35-induced reduction of synapse-related proteins VAMP2 and PSD95 in primary neurons through enhancing ERβ/BDNF/TrkB/CREB pathways; PTA treatment alleviated o-Aβ25-35-induced oxidative stress in primary neurons through targeting ERβ and increasing Catalase expression. Together, this study has addressed the efficacy of selective ERβ agonist in the amelioration of AD and highlighted the potential of PTA as a drug lead compound against the disease.

Project description:AimStreptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice.MethodsCell-based assays for screening anti-amyloid compounds were established by assessing Aβ accumulation in HEK293-APPsw and CHO-APP cells, and Aβ clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate Aβ and sAPPβ levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains.ResultsLX2343 (5-20 μmol/L) dose-dependently decreased Aβ accumulation in HEK293-APPsw and CHO-APP cells, and promoted Aβ clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 μmol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing Aβ clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the Aβ pathology in their brains.ConclusionLX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both Aβ production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.

Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.

Dataset Information

SPIN90 Deficiency Ameliorates Amyloid β Accumulation by Regulating APP Trafficking in AD Model Mice.

Publications

SPIN90 Deficiency Ameliorates Amyloid β Accumulation by Regulating APP Trafficking in AD Model Mice.

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