MSR1 and NEP Are Correlated with Alzheimer’s Disease Amyloid Pathology and Apolipoprotein Alterations

2022 ◽  
pp. 1-13
Author(s):  
Justin Miron ◽  
Cynthia Picard ◽  
Anne Labonté ◽  
Daniel Auld ◽  
Judes Poirier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Levels ◽  
Disease Stage ◽  
Mrna Levels ◽  
Strongly Correlated ◽  
Csf Levels ◽  
Barrier Breakdown ◽  
Highly Correlated ◽  
Apoe Mrna

Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ 1 - 42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aβ 1 - 42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1, APOE, and CLU (ApoJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aβ 1 - 42, ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. Conclusion: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aβ 1 - 42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages.

scholarly journals Quantitative Measurement of Cerebrospinal Fluid Amyloid-β Species by Mass Spectrometry

2020 ◽  
pp. 1-12
Author(s):  
Yusuke Seino ◽  
Takumi Nakamura ◽  
Tomoo Harada ◽  
Naoko Nakahata ◽  
Takeshi Kawarabayashi ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Quantitative Measurement ◽  
Amyloid Β ◽  
High Sensitivity ◽  
Csf Biomarkers ◽  
Strongly Correlated ◽  
Csf Levels

Background: High sensitivity liquid chromatography mass spectrometry (LC-MS/MS) was recently introduced to measure amyloid-β (Aβ) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. Objective: We validated the Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 assay by LC-MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application. Methods: CSF samples from 120 subjects [8 Alzheimer’s disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer’s disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC-MS/MS system. Aβ1-40 and Aβ1-42 levels were validated using ELISA. Results: CSF levels in CU were 666±249 pmol/L in Aβ1-38, 2199±725 pmol/L in Aβ1-40, 153.7±79.7 pmol/L in Aβ1-42, and 9.78±4.58 pmol/L in Aβ1-43. The ratio of the amounts of Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aβ species. Both Aβ1-40 and Aβ1-42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aβ1-38 or Aβ1-40 levels between AD and CU. Aβ1-42 and Aβ1-43 levels were significantly lower, whereas the Aβ1-38/1-42, Aβ1-38/1-43, and Aβ1-40/Aβ1-43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aβ species were adequate for clinical usage. Conclusion: A quantitative LC-MS/MS assay of CSF Aβ species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD.

scholarly journals Identifying Blood Transcriptome Biomarkers of Alzheimer’s Disease Using Transgenic Mice

2020 ◽  
Vol 57 (12) ◽  
pp. 4941-4951
Author(s):  
Shinichiro Ochi ◽  
Jun-ichi Iga ◽  
Yu Funahashi ◽  
Yuta Yoshino ◽  
Kiyohiro Yamazaki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Mrna Levels ◽  
Mouse Blood ◽  
Gene Transcripts ◽  
Functional Analyses ◽  
And Control ◽  
Apoe Mrna ◽  
Blood Transcriptome

Abstract The testing of pathological biomarkers of Alzheimer’s disease (AD), such as amyloid beta and tau, is time-consuming, expensive, and invasive. Here, we used 3xTg-AD mice to identify and validate putative novel blood transcriptome biomarkers of AD that can potentially be identified in the blood of patients. mRNA was extracted from the blood and hippocampus of 3xTg-AD and control mice at different ages and used for microarray analysis. Network and functional analyses revealed that the differentially expressed genes between AD and control mice modulated the immune and neuroinflammation systems. Five novel gene transcripts (Cdkn2a, Apobec3, Magi2, Parp3, and Cass4) showed significant increases with age, and their expression in the blood was collated with that in the hippocampus only in AD mice. We further assessed previously identified candidate biomarker genes. The expression of Trem1 and Trem2 in both the blood and brain was significantly increased with age. Decreased Tomm40 and increased Pink1 mRNA levels were observed in the mouse blood. The changes in the expression of Snca and Apoe mRNA in the mouse blood and brain were similar to those found in human AD blood. Our results demonstrated that the immune and neuroinflammatory system is involved in the pathophysiologies of aging and AD and that the blood transcriptome might be useful as a biomarker of AD.

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

scholarly journals Role of the lncRNA BACE1-AS in shared disease mechanisms between heart failure and Alzheimer's disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Greco ◽  
A Made' ◽  
A.S Tascini ◽  
J Garcia Manteiga ◽  
S Castelvecchio ◽  
...  
Keyword(s):  
Heart Failure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Situ Hybridization ◽  
Cell Apoptosis ◽  
Common Disease ◽  
Funding Source ◽  
Mrna Levels ◽  
Rna Seq

Abstract Background BACE1 encodes for β-secretase, the key enzyme involved in β-amyloid (βA) generation, a peptide well known for its involvement in Alzheimer's disease (AD). Of note, heart failure (HF) and AD share several risk factors and effectors. We recently showed that, in the heart of ischemic HF patients, the levels of both BACE1, its antisense RNA BACE1-AS and βA are all increased. BACE1-AS positively regulates the expression of BACE1, triggering βA intracellular accumulation, and its overexpression or βA administration induce cardiovascular-cell apoptosis. Aim To characterize the transcripts of the BACE1 locus and to investigate the molecular mechanisms underpinning BACE1-AS regulation of cell vitality. Methods By PCR and sequencing, we studied in the heart the expression of a variety of antisense BACE1 transcripts predicted by FANTOM CAT Epigenome. We studied BACE1 RNA stability by BrdU pulse chase experiments (BRIC assay). The cellular localization of BACE1-AS RNA was investigated by in situ hybridization assay. BACE1-AS binding RNAs were evaluated by BACE1-AS-MS2-Tag pull-down in AC16 cardiomyocytes followed by RNA-seq. Enriched RNAs were validated by qPCR and analysed by bioinformatics comparison with publicly available gene expression datasets of AD brains. Results We readily detected several antisense BACE1 transcripts expressed in AC16 cardiomyocytes; however, only BACE1-AS RNAs overlapping exon 6 of BACE1 positively regulated BACE1 mRNA levels, acting by increasing its stability. BACE1 silencing reverted cell apoptosis induced by BACE1-AS expression, indicating that BACE1 is a functional target of BACE1-AS. However, in situ hybridization experiments indicated a mainly nuclear localization for BACE1-AS, which displayed a punctuated distribution, compatible with chromatin association and indicative of potential additional targets. To identify other BACE1-AS binding RNAs, a BACE1-AS-MS2-tag pull-down was performed and RNA-seq of the enriched RNAs identified 698 BACE1-AS interacting RNAs in cardiomyocytes. Gene ontology of the BACE1-AS binding RNAs identified categories of relevance for cardiovascular or neurological diseases, such as dopaminergic synapse, glutamatergic synapse, calcium signalling pathway and voltage-gated channel activity. In spite of the differences between brain and heart transcriptomes, BACE1-AS-interacting RNAs identified in cardiomyocytes were significantly enriched in transcripts differentially expressed in AD brains as well as in RNAs expressed by enhancer genomic regions that are significantly hypomethylated in AD brains. Conclusions These data shed a new light on the complexity of BACE1-AS locus and on the existence of RNAs interacting with BACE1-AS with a potential as enhancer-RNAs. Moreover, the dysregulation of the BACE1-AS/BACE1/βA pathway may be a common disease mechanism shared by cardiovascular and neurological degenerative diseases. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Health Ministery_Ricerca Corrente 2020

scholarly journals Quantitative Longitudinal Predictions of Alzheimer’s Disease by Multi-Modal Predictive Learning

2021 ◽  
Vol 79 (4) ◽  
pp. 1533-1546
Author(s):  
Mithilesh Prakash ◽  
Mahmoud Abdelaziz ◽  
Linda Zhang ◽  
Bryan A. Strange ◽  
Jussi Tohka ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prediction Models ◽  
Predictive Performance ◽  
Absolute Error ◽  
Disease Stage ◽  
Disease Assessment ◽  
Disease Category ◽  
Modal Data ◽  
Predictive Learning

Background: Quantitatively predicting the progression of Alzheimer’s disease (AD) in an individual on a continuous scale, such as the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) scores, is informative for a personalized approach as opposed to qualitatively classifying the individual into a broad disease category. Objective: To evaluate the hypothesis that the multi-modal data and predictive learning models can be employed for future predicting ADAS-cog scores. Methods: Unimodal and multi-modal regression models were trained on baseline data comprised of demographics, neuroimaging, and cerebrospinal fluid based markers, and genetic factors to predict future ADAS-cog scores for 12, 24, and 36 months. We subjected the prediction models to repeated cross-validation and assessed the resulting mean absolute error (MAE) and cross-validated correlation (ρ) of the model. Results: Prediction models trained on multi-modal data outperformed the models trained on single modal data in predicting future ADAS-cog scores (MAE12, 24 & 36 months= 4.1, 4.5, and 5.0, ρ12, 24 & 36 months= 0.88, 0.82, and 0.75). Including baseline ADAS-cog scores to prediction models improved predictive performance (MAE12, 24 & 36 months= 3.5, 3.7, and 4.6, ρ12, 24 & 36 months= 0.89, 0.87, and 0.80). Conclusion: Future ADAS-cog scores were predicted which could aid clinicians in identifying those at greater risk of decline and apply interventions at an earlier disease stage and inform likely future disease progression in individuals enrolled in AD clinical trials.

scholarly journals ADeditome provides the genomic landscape of A-to-I RNA editing in Alzheimer’s disease

2021 ◽  
Author(s):  
Sijia Wu ◽  
Mengyuan Yang ◽  
Pora Kim ◽  
Xiaobo Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Editing ◽  
Memory Loss ◽  
Brain Regions ◽  
Disease Stage ◽  
Mirna Regulation ◽  
Annotation Database ◽  
Functional Annotations ◽  
Genomic Landscape

Abstract A-to-I RNA editing, contributing to nearly 90% of all editing events in human, has been reported to involve in the pathogenesis of Alzheimer’s disease (AD) due to its roles in brain development and immune regulation, such as the deficient editing of GluA2 Q/R related to cell death and memory loss. Currently, there are urgent needs for the systematic annotations of A-to-I RNA editing events in AD. Here, we built ADeditome, the annotation database of A-to-I RNA editing in AD available at https://ccsm.uth.edu/ADeditome, aiming to provide a resource and reference for functional annotation of A-to-I RNA editing in AD to identify therapeutically targetable genes in an individual. We detected 1676 363 editing sites in 1524 samples across nine brain regions from ROSMAP, MayoRNAseq and MSBB. For these editing events, we performed multiple functional annotations including identification of specific and disease stage associated editing events and the influence of editing events on gene expression, protein recoding, alternative splicing and miRNA regulation for all the genes, especially for AD-related genes in order to explore the pathology of AD. Combing all the analysis results, we found 108 010 and 26 168 editing events which may promote or inhibit AD progression, respectively. We also found 5582 brain region-specific editing events with potentially dual roles in AD across different brain regions. ADeditome will be a unique resource for AD and drug research communities to identify therapeutically targetable editing events. Significance: ADeditome is the first comprehensive resource of the functional genomics of individual A-to-I RNA editing events in AD, which will be useful for many researchers in the fields of AD pathology, precision medicine, and therapeutic researches.

scholarly journals Platelet APP‐ratio correlates with CSF levels of Aβ1‐42 in Alzheimer’s disease patients

2020 ◽  
Vol 16 (S5) ◽  
Author(s):  
Tamires Alves Sarno ◽  
Leda Leme Talib ◽  
Helena Passarelli Giroud Joaquim ◽  
Marcia Radanovic ◽  
Jessyka Maria de França Bram ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Csf Levels ◽  
App Ratio

scholarly journals Association of naturally occurring antibodies to β-amyloid with cognitive decline and cerebral amyloidosis in Alzheimer’s disease

2021 ◽  
Vol 7 (1) ◽  
pp. eabb0457
Author(s):  
Yu-Hui Liu ◽  
Jun Wang ◽  
Qiao-Xin Li ◽  
Christopher J. Fowler ◽  
Fan Zeng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Plasma Levels ◽  
Imaging Biomarkers ◽  
Amino Terminus ◽  
Cross Sectional ◽  
Naturally Occurring ◽  
Β Amyloid ◽  
Naturally Occurring Antibodies

The pathological relevance of naturally occurring antibodies to β-amyloid (NAbs-Aβ) in Alzheimer’s disease (AD) remains unclear. We aimed to investigate their levels and associations with Aβ burden and cognitive decline in AD in a cross-sectional cohort from China and a longitudinal cohort from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. NAbs-Aβ levels in plasma and cerebrospinal fluid (CSF) were tested according to their epitopes. Levels of NAbs targeting the amino terminus of Aβ increased, and those targeting the mid-domain of Aβ decreased in both CSF and plasma in AD patients. Higher plasma levels of NAbs targeting the amino terminus of Aβ and lower plasma levels of NAbs targeting the mid-domain of Aβ were associated with higher brain amyloidosis at baseline and faster cognitive decline during follow-up. Our findings suggest a dynamic response of the adaptive immune system in the progression of AD and are relevant to current passive immunotherapeutic strategies.

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