Finding New Ways How to Control BACE1

Nahálková, Jarmila

doi:10.1007/s00232-022-00225-1

Cited by 4 publications

(3 citation statements)

References 223 publications

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“…Conversely y, in AD, amyloid precursor proteins form a trimeric complex composed of PP1 and Fe65, with PP1 dephosphorylating APP at Thr668 residues. BRI3 is also a signi cant substrate of protein phosphatase 1, contributing to the dephosphorylation process of APP [39,40]. The SPTSSA substrate plays a crucial role in the serine palmitoyl transferase (SPT) complex.…”

Section: Discussionmentioning

confidence: 99%

The diagnostic value of blood miR-132-3p level in patients with Alzheimer's disease

Zhang,

Fu,

Ren

et al. 2024

Preprint

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Objective: To investigate the relationship between miR-132-3p level in circulating blood and the degree of cognitive impairment and hippocampal atrophy in Alzheimer's disease (AD) patients, as well as its diagnostic value. Methods: The expression level of miR-132-3p in brain tissue between early and late AD patients and between AD patients and normal subjects was verified using GEO datasets. By collecting blood samples and various data from AD patients and normal subjects, the changes of miR-132-3p in blood in AD were analyzed. A total of 50 AD patients and 50 healthy individuals were recruited from the Memory Clinic of the Neurology Department of the Affiliated Hospital of Binzhou Medical College between January 2021 and January 2023. All patients underwent cognitive function tests and MRIs. The height of the hippocampus and the width of the temporal horn were measured linearly, and the volume of the hippocampus was calculated using the MTA visual score system. RT-PCR was used to detect the expression levels ofmiR-132-3p in patient blood. Pearson and Spearman correlation coefficient were used for correlation analysis. Finally, the miRNA target gene of Alzheimer's disease was predicted through a cross-analysis using the miRDB and TargetScan prediction websites, as well as the SE29378 dataset from GEO. Results: 1. According to the data analysis, miR-132-3p in the prefrontal cortex was significantly decreased in the late AD period (p<0.001). The expression of miR-132-3p in the temporal cortex and cerebrospinal fluid of AD patients exhibited a decreasing trend compared to that of healthy individuals. 2. MiR-132-3p expression level in the blood of AD patients was significantly lower compared with that of healthy individuals (p<0.001). 3. The hippocampal height, MMSE score, and MoCA score were significantly lower while temporal horn width and MTA score were significantly higher in AD patients than in healthy individuals (p＜0.001). 4. MiR-132-3p expression in blood was positively correlated with MMSE score, MoCA score, and hippocampal height (rMMSE2=0.5067, rMoCA2=0.6101, rHippocampal height2 =0.6686; p<0.001), but negatively correlated with MTA score and temporal horn width (rMTA score2 =0.1699, rTemporal Angle width2 =0.2922; p<0.001). 5. ROC curve analysis revealed that when the optimal cut-off value was 0.6944, the area under the curve of blood miR-132-3p expression, sensitivity and specificity values for AD diagnosis were 0.7640, 74.00%, and 70.00%, respectively. 6. By integrating the three datasets and conducting cross-analysis, we identified two genes, BRI3 and SPTSSA, as the targets of miRNA involved in AD. Conclusion: The expression of miR-132-3p in all brain regions of AD patients exhibited a significant decrease, with lower levels observed in the late stage compared to the early stage of the disease. Experimental detection also revealed a significant reduction in miR-132-3p expression in the blood of AD patients, which correlated with hippocampus atrophy and cognitive function assessed by brain MRI. It is suggested that blood miR-132-3p levels could serve as a potential clinical diagnostic indicator. Cross-analysis of gene data sets indicates that BRI3 and SPTSSA may be target genes through which miR-132-3p affects AD.

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Section: Discussionmentioning

confidence: 99%

The diagnostic value of blood miR-132-3p level in patients with Alzheimer's disease

Zhang,

Fu,

Ren

et al. 2024

Preprint

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“…Current strategies regarding the inhibition of APP processing by altering glycosylation have focused on the regulation of hydrolases, such as the curcumin derivative GT863. In addition, considering that previous inhibitors designed for BACE1 have been reported to generate serious side effects, a selective modulation of the cleavage activity of BACE1 by altering the glycosylation pattern (such as modulating galactosyltransferases and mannosidases) to regulate the effects of glycosylases is being considered as a promising and novel therapeutic modality for AD ( Nahálková, 2022 ).…”

Section: Glycosylation Is Involved In the Pathogenesis And Etiology O...mentioning

confidence: 99%

The alteration and role of glycoconjugates in Alzheimer’s disease

Kang,

Zhang,

et al. 2024

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by abnormal protein deposition. With an alarming 30 million people affected worldwide, AD poses a significant public health concern. While inhibiting key enzymes such as β-site amyloid precursor protein-cleaving enzyme 1 and γ-secretase or enhancing amyloid-β clearance, has been considered the reasonable strategy for AD treatment, their efficacy has been compromised by ineffectiveness. Furthermore, our understanding of AD pathogenesis remains incomplete. Normal aging is associated with a decline in glucose uptake in the brain, a process exacerbated in patients with AD, leading to significant impairment of a critical post-translational modification: glycosylation. Glycosylation, a finely regulated mechanism of intracellular secondary protein processing, plays a pivotal role in regulating essential functions such as synaptogenesis, neurogenesis, axon guidance, as well as learning and memory within the central nervous system. Advanced glycomic analysis has unveiled that abnormal glycosylation of key AD-related proteins closely correlates with the onset and progression of the disease. In this context, we aimed to delve into the intricate role and underlying mechanisms of glycosylation in the etiopathology and pathogenesis of AD. By highlighting the potential of targeting glycosylation as a promising and alternative therapeutic avenue for managing AD, we strive to contribute to the advancement of treatment strategies for this debilitating condition.

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“…In addition, previous inhibitors designed for BACE1 with β-secretase activity often interfere with its processing of other substrates, producing severe side effects. Selective modulation of BACE1 cleavage activity towards APP by altering the glycosylation of BACE1 is considered as a promising AD therapeutic modality [ 51 ]. The regulation of BACE1 glycosylation can be achieved by the regulatory action of various glycosylases such as galactosyltransferases and mannosidases.…”

Section: Introductionmentioning

confidence: 99%

New insight into protein glycosylation in the development of Alzheimer’s disease

Zhao,

Lang

2023

Cell Death Discov.

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease that seriously endangers the physical and mental health of patients, however, there are still no effective drugs or methods to cure this disease up to now. Protein glycosylation is the most common modifications of the translated proteins in eukaryotic cells. Recently many researches disclosed that aberrant glycosylation happens in some important AD-related proteins, such as APP, Tau, Reelin and CRMP-2, etc, suggesting a close link between abnormal protein glycosylation and AD. Because of its complexity and diversity, glycosylation is thus considered a completely new entry point for understanding the precise cause of AD. This review comprehensively summarized the currently discovered changes in protein glycosylation patterns in AD, and especially introduced the latest progress on the mechanism of protein glycosylation affecting the progression of AD and the potential application of protein glycosylation in AD detection and treatment, thereby providing a wide range of opportunities for uncovering the pathogenesis of AD and promoting the translation of glycosylation research into future clinical applications.

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Finding New Ways How to Control BACE1

Cited by 4 publications

References 223 publications

The diagnostic value of blood miR-132-3p level in patients with Alzheimer's disease

The diagnostic value of blood miR-132-3p level in patients with Alzheimer's disease

The alteration and role of glycoconjugates in Alzheimer’s disease

New insight into protein glycosylation in the development of Alzheimer’s disease

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