scholarly journals Connection between the Altered HDL Antioxidant and Anti-Inflammatory Properties and the Risk to Develop Alzheimer’s Disease: A Narrative Review

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Francesca Zimetti ◽  
Maria Pia Adorni ◽  
Judit Marsillach ◽  
Cinzia Marchi ◽  
Alessandro Trentini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Density Lipoprotein ◽  
Protein Composition ◽  
Paraoxonase 1 ◽  
Amyloid A ◽  
Proinflammatory Mediators ◽  
Associated Proteins ◽  
Defensive Action

The protein composition of high-density lipoprotein (HDL) is extremely fluid. The quantity and quality of protein constituents drive the multiple biological functions of these lipoproteins, which include the ability to contrast atherogenesis, sustained inflammation, and toxic effects of reactive species. Several diseases where inflammation and oxidative stress participate in the pathogenetic process are characterized by perturbation in the HDL proteome. This change inevitably affects the functionality of the lipoprotein. An enlightening example in this frame comes from the literature on Alzheimer’s disease (AD). Growing lines of epidemiological evidence suggest that loss of HDL-associated proteins, such as lipoprotein phospholipase A2 (Lp-PLA2), glutathione peroxidase-3 (GPx-3), and paraoxonase-1 and paraoxonase-3 (PON1, PON3), may be a feature of AD, even at the early stage. Moreover, the decrease in these enzymes with antioxidant/defensive action appears to be accompanied by a parallel increase of prooxidant and proinflammatory mediators, in particular myeloperoxidase (MPO) and serum amyloid A (SAA). This type of derangement of balance between two opposite forces makes HDL dysfunctional, i.e., unable to exert its “natural” vasculoprotective property. In this review, we summarized and critically analyzed the most significant findings linking HDL accessory proteins and AD. We also discuss the most convincing hypothesis explaining the mechanism by which an observed systemic occurrence may have repercussions in the brain.

scholarly journals HDL Proteome and Alzheimer’s Disease: Evidence of a Link

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1224
Author(s):  
Judit Marsillach ◽  
Maria Pia Adorni ◽  
Francesca Zimetti ◽  
Bianca Papotti ◽  
Giovanni Zuliani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Density Lipoprotein ◽  
Paraoxonase 1 ◽  
Beneficial Effects ◽  
Current State ◽  
Associated Proteins ◽  
Main Determinants ◽  
The Brain

Several lines of epidemiological evidence link increased levels of high-density lipoprotein-cholesterol (HDL-C) with lower risk of Alzheimer’s disease (AD). This observed relationship might reflect the beneficial effects of HDL on the cardiovascular system, likely due to the implication of vascular dysregulation in AD development. The atheroprotective properties of this lipoprotein are mostly due to its proteome. In particular, apolipoprotein (Apo) A-I, E, and J and the antioxidant accessory protein paraoxonase 1 (PON1), are the main determinants of the biological function of HDL. Intriguingly, these HDL constituent proteins are also present in the brain, either from in situ expression, or derived from the periphery. Growing preclinical evidence suggests that these HDL proteins may prevent the aberrant changes in the brain that characterize AD pathogenesis. In the present review, we summarize and critically examine the current state of knowledge on the role of these atheroprotective HDL-associated proteins in AD pathogenesis and physiopathology.

scholarly journals Large-scale proteome analysis of CSF implicates altered glucose metabolism in Alzheimer's disease

2021 ◽  
Author(s):  
Daniel J. Panyard ◽  
Justin McKetney ◽  
Yuetiva K. Deming ◽  
Autumn R. Morrow ◽  
Gilda E. Ennis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Multiple Testing ◽  
Large Scale ◽  
Csf Biomarkers ◽  
Multiple Testing Correction ◽  
Comparative Performance ◽  
Amyloid A ◽  
Altered Glucose ◽  
Associated Proteins

A major hallmark of Alzheimer's disease (AD) is the aggregation of misfolded proteins (β-amyloid (A) and hyperphosphorylated tau (T)) in the brain. As these proteins can be monitored by cerebrospinal fluid (CSF) measures, the AD proteome in CSF has been of particular interest. Here, we conducted a proteome-wide assessment of the CSF in an AD cohort among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), identifying a diverse set of proteins in the CSF enriched for extracellular and immune system processes. We then interrogated the proteome using the amyloid, tau, and neurodegeneration (ATN) framework of AD and a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. After multiple testing correction, we identified a total of 61 proteins significantly associated with AT group (P < 5.46 x 10-5; strongest was SMOC1, P = 1.87 x 10-12) and 636 significant protein-biomarker associations (P < 6.07 x 10-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 x 10-25) across all measures except for interleukin-6, which had no significantly associated proteins. Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks: one related to amyloid and tau measures, one to CSF neurogranin, and one to the remaining CSF biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were replicated as strongly associated with AD (P = 1.07 x 10-19 and P = 7.43 x 10-14, respectively) in an independent CSF proteomics cohort (n = 717 participants). Comparative performance of the CSF proteome in predicting AT categorization was high (mean AUC range 0.891-0.924 with number of protein predictors ranging from 37-97) relative to other omic predictors from the genome, CSF metabolome, and demographics from the same cohort of individuals. Collectively, these results emphasize the importance of the CSF proteome relative to other omics and implicate glucose metabolic dysregulation as amyloid and tau pathology emerges in AD.

scholarly journals Looking for a Treatment for the Early Stage of Alzheimer’s Disease: Preclinical Evidence with Co-Ultramicronized Palmitoylethanolamide and Luteolin

2020 ◽  
Vol 21 (11) ◽  
pp. 3802 ◽  
Author(s):  
Roberta Facchinetti ◽  
Marta Valenza ◽  
Maria Rosanna Bronzuoli ◽  
Giorgia Menegoni ◽  
Patrizia Ratano ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Early Stage ◽  
Neuroprotective Effect ◽  
Pharmacological Study ◽  
Mrna Levels ◽  
Prodromal Stage ◽  
Term Care ◽  
Proinflammatory Mediators

Background: At the earliest stage of Alzheimer’s disease (AD), although patients are still asymptomatic, cerebral alterations have already been triggered. In addition to beta amyloid (Aβ) accumulation, both glial alterations and neuroinflammation have been documented at this stage. Starting treatment at this prodromal AD stage could be a valuable therapeutic strategy. AD requires long-term care; therefore, only compounds with a high safety profile can be used, such as the new formulation containing palmitoylethanolamide and luteolin (co-ultra PEALut) already approved for human use. Therefore, we investigated it in an in vivo pharmacological study that focused on the prodromal stage of AD. Methods: We tested the anti-inflammatory and neuroprotective effects of co-ultra PEALut (5 mg/Kg) administered for 14 days in rats that received once, 5 µg Aβ(1–42) into the hippocampus. Results: Glial activation and elevated levels of proinflammatory mediators were observed in Aβ-infused rats. Early administration of co-ultra PEALut prevented the Aβ-induced astrogliosis and microgliosis, the upregulation in gene expression of pro-inflammatory cytokines and enzymes, as well as the reduction of mRNA levels BDNF and GDNF. Our findings also highlight an important neuroprotective effect of co-ultra PEALut treatment, which promoted neuronal survival. Conclusions: Our results reveal the presence of cellular and molecular modifications in the prodromal stage of AD. Moreover, the data presented here demonstrate the ability of co-ultra PEALut to normalize such Aβ-induced alterations, suggesting it as a valuable therapeutic strategy.

Fluoxetine Protects against Dendritic Spine Loss in Middle-aged APPswe/PSEN1dE9 Double Transgenic Alzheimer’s Disease Mice

2020 ◽  
Vol 17 (1) ◽  
pp. 93-103 ◽  
Author(s):  
Jing Ma ◽  
Yuan Gao ◽  
Wei Tang ◽  
Wei Huang ◽  
Yong Tang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Early Stage ◽  
Learning Ability ◽  
Middle Aged ◽  
Protein Levels ◽  
Spine Pathology ◽  
The Impact

Background: Studies have suggested that cognitive impairment in Alzheimer’s disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice. Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice. Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus. Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.

scholarly journals Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao Hu ◽  
Lan Tan ◽  
Yan-Lin Bi ◽  
Wei Xu ◽  
Lin Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peripheral Blood ◽  
Late Onset ◽  
Early Stage ◽  
Susceptibility Gene ◽  
Subjective Cognitive Decline ◽  
Preclinical Ad ◽  
T Tau ◽  
New Evidence

AbstractThe bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer’s disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

scholarly journals Plasma contact factors as novel biomarkers for diagnosing Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jung Eun Park ◽  
Do Sung Lim ◽  
Yeong Hee Cho ◽  
Kyu Yeong Choi ◽  
Jang Jae Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Clinical Stage ◽  
Area Under The Curve ◽  
Contact System ◽  
Plasma Diagnostic ◽  
Vascular Abnormalities ◽  
Prodromal Ad ◽  
Novel Biomarkers

Abstract Background Alzheimer’s disease (AD) is the most common cause of dementia and most of AD patients suffer from vascular abnormalities and neuroinflammation. There is an urgent need to develop novel blood biomarkers capable of diagnosing Alzheimer’s disease (AD) at very early stage. This study was performed to find out new accurate plasma diagnostic biomarkers for AD by investigating a direct relationship between plasma contact system and AD. Methods A total 101 of human CSF and plasma samples from normal and AD patients were analyzed. The contact factor activities in plasma were measured with the corresponding specific peptide substrates. Results The activities of contact factors (FXIIa, FXIa, plasma kallikrein) and FXa clearly increased and statistically correlated as AD progresses. We present here, for the first time, the FXIIa cut-off scores to as: > 26.3 U/ml for prodromal AD [area under the curve (AUC) = 0.783, p < 0.001] and > 27.2 U/ml for AD dementia (AUC = 0.906, p < 0.001). We also describe the cut-off scores from the ratios of CSF Aβ1–42 versus the contact factors. Of these, the representative ratio cut-off scores of Aβ1–42/FXIIa were to be: < 33.8 for prodromal AD (AUC = 0.965, p < 0.001) and < 27.44 for AD dementia (AUC = 1.0, p < 0.001). Conclusion The activation of plasma contact system is closely associated with clinical stage of AD, and FXIIa activity as well as the cut-off scores of CSF Aβ1–42/FXIIa can be used as novel accurate diagnostic AD biomarkers.

scholarly journals Early Detection of Alzheimer’s Disease Using Polar Harmonic Transforms and Optimized Wavelet Neural Network

2021 ◽  
Vol 11 (4) ◽  
pp. 1574
Author(s):  
Shabana Urooj ◽  
Satya P. Singh ◽  
Areej Malibari ◽  
Fadwa Alrowais ◽  
Shaeen Kalathil
Keyword(s):  
Neural Network ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Detection ◽  
Differential Evolution ◽  
Early Stage ◽  
Selection Process ◽  
Parameter Tuning ◽  
Wavelet Neural Network ◽  
Tuning Parameter

Effective and accurate diagnosis of Alzheimer’s disease (AD), as well as early-stage detection, has gained more and more attention in recent years. For AD classification, we propose a new hybrid method for early detection of Alzheimer’s disease (AD) using Polar Harmonic Transforms (PHT) and Self-adaptive Differential Evolution Wavelet Neural Network (SaDE-WNN). The orthogonal moments are used for feature extraction from the grey matter tissues of structural Magnetic Resonance Imaging (MRI) data. Irrelevant features are removed by the feature selection process through evaluating the in-class and among-class variance. In recent years, WNNs have gained attention in classification tasks; however, they suffer from the problem of initial parameter tuning, parameter setting. We proposed a WNN with the self-adaptation technique for controlling the Differential Evolution (DE) parameters, i.e., the mutation scale factor (F) and the cross-over rate (CR). Experimental results on the Alzheimer’s disease Neuroimaging Initiative (ADNI) database indicate that the proposed method yields the best overall classification results between AD and mild cognitive impairment (MCI) (93.7% accuracy, 86.0% sensitivity, 98.0% specificity, and 0.97 area under the curve (AUC)), MCI and healthy control (HC) (92.9% accuracy, 95.2% sensitivity, 88.9% specificity, and 0.98 AUC), and AD and HC (94.4% accuracy, 88.7% sensitivity, 98.9% specificity and 0.99 AUC).

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