Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: implications for lipid antioxidant activity and Alzheimer's disease

ApoD (apolipoprotein D) is up-regulated in AD (Alzheimer's disease) and upon oxidative stress. ApoD inhibits brain lipid peroxidation in vivo, but the mechanism is unknown. Specific methionine residues may inhibit lipid peroxidation by reducing radical-propagating L-OOHs (lipid hydroperoxides) to non-reactive hydroxides via a reaction that generates MetSO (methionine sulfoxide). Since apoD has three conserved methionine residues (Met49, Met93 and Met157), we generated recombinant proteins with either one or all methionine residues replaced by alanine and assessed their capacity to reduce HpETEs (hydroperoxyeicosatetraenoic acids) to their HETE (hydroxyeicosatetraenoic acid) derivatives. ApoD, apoDM49-A and apoDM157-A all catalysed the reduction of HpETEs to their corresponding HETEs. Amino acid analysis of HpETE-treated apoD revealed a loss of one third of the methionine residues accompanied by the formation of MetSO. Additional studies using apoD(M93-A) indicated that Met93 was required for HpETE reduction. We also assessed the impact that apoD MetSO formation has on protein aggregation by Western blotting of HpETE-treated apoD and human brain samples. ApoD methionine oxidation was associated with formation of apoD aggregates that were also detected in the hippocampus of AD patients. In conclusion, conversion of HpETE into HETE is mediated by apoD Met93, a process that may contribute to apoD antioxidant function.

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Anti-Inflammatory Activity of A Polyphenolic Extract from Arabidopsis thaliana in In Vitro and In Vivo Models of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20030708 ◽

2019 ◽

Vol 20 (3) ◽

pp. 708 ◽

Cited By ~ 12

Author(s):

Roberto Mattioli ◽

Antonio Francioso ◽

Maria d’Erme ◽

Maurizio Trovato ◽

Patrizia Mancini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Arabidopsis Thaliana ◽

Heme Oxygenase 1 ◽

Neuroprotective Effects ◽

In Vivo Models ◽

Polyphenolic Extract ◽

Anti Inflammatory ◽

The Impact

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of Arabidopsis thaliana (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ25–35 peptide and extract showed a lower pro-inflammatory (IL-6, IL-1β, TNF-α) and a higher anti-inflammatory (IL-4, IL-10, IL-13) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ1–42. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases.

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Methionine sulfoxide reductase A affects β-amyloid solubility and mitochondrial function in a mouse model of Alzheimer's disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00453.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. E388-E393 ◽

Cited By ~ 11

Author(s):

Jackob Moskovitz ◽

Fang Du ◽

Connor F. Bowman ◽

Shirley S. Yan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Methionine Sulfoxide ◽

Methionine Sulfoxide Reductase ◽

Methionine Sulfoxide Reductase A ◽

Model Of Alzheimer’S Disease ◽

Amyloid Aβ ◽

Β Amyloid

Accumulation of oxidized proteins, and especially β-amyloid (Aβ), is thought to be one of the common causes of Alzheimer's disease (AD). The current studies determine the effect of an in vivo methionine sulfoxidation of Aβ through ablation of the methionine sulfoxide reductase A (MsrA) in a mouse model of AD, a mouse that overexpresses amyloid precursor protein (APP) and Aβ in neurons. Lack of MsrA fosters the formation of methionine sulfoxide in proteins, and thus its ablation in the AD-mouse model will increase the formation of methionine sulfoxide in Aβ. Indeed, the novel MsrA-deficient APP mice ( APP+/ MsrAKO) exhibited higher levels of soluble Aβ in brain compared with APP+ mice. Furthermore, mitochondrial respiration and the activity of cytochrome c oxidase were compromised in the APP+/ MsrAKO compared with control mice. These results suggest that lower MsrA activity modifies Aβ solubility properties and causes mitochondrial dysfunction, and augmenting its activity may be beneficial in delaying AD progression.

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Cholesterol Alters Mitophagy by Impairing Optineurin Recruitment and Lysosomal Clearance in Alzheimer’s Disease

10.21203/rs.3.rs-69969/v1 ◽

2020 ◽

Author(s):

Vicente Roca-Agujetas ◽

Elisabet Barbero-Camps ◽

Cristina de Dios ◽

Petar Podlesniy ◽

Albert Morales ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholesterol Homeostasis ◽

Critical Event ◽

Primary Neurons ◽

Cholesterol Levels ◽

Swedish Mutation ◽

Intracellular Cholesterol ◽

The Impact

Abstract Background: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer’s disease (AD) pathogenesis. Amyloid-beta (A) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low A clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.Methods: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.Results: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by A while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages. Conclusions: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

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Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer’s disease

Molecular Neurodegeneration ◽

10.1186/s13024-021-00473-0 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Christel Claes ◽

Emma Pascal Danhash ◽

Jonathan Hasselmann ◽

Jean Paul Chadarevian ◽

Sepideh Kiani Shabestari ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipid Droplet ◽

Lipid Droplets ◽

Foam Cells ◽

Wild Type ◽

Human Microglia ◽

Model Of Alzheimer’S Disease ◽

The Impact

Abstract Background Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer’s disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown. Methods To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed. Results Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE. Conclusions Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.

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A General Approach to Convert Hemicyanine Dyes into Highly Optimized Photoacoustic Scaffolds for Analyte Sensing

10.26434/chemrxiv.14494383.v1 ◽

2021 ◽

Author(s):

Sarah Garder ◽

Catharine Brady ◽

Cameron Keeton ◽

Anuj K Yadav ◽

Sharath C Mallojjala ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Photoacoustic Imaging ◽

Disease Model ◽

Photoacoustic Signal ◽

Model Of Alzheimer’S Disease ◽

5Xfad Mice ◽

The Impact

In the context of deep-tissue disease biomarker detection and analyte sensing of biologically relevant species, the impact of photoacoustic imaging has been profound. However, most photoacoustic imaging agents to date are based on the repurposing of existing fluorescent dye platforms that exhibit non-optimal properties for photoacoustic applications (e.g., high fluorescence quantum yield). Herein, we introduce two effective modifications to the hemicyanine dye to afford PA-HD, a new dye scaffold optimized for photoacoustic probe development. We observed a significant increase in the photoacoustic output, representing an increase in sensitivity of 4.8-fold and a red-shift of the λabs from 690 nm to 745 nm to enable ratiometric imaging. Moreover, to demonstrate the generalizability and utility of our remodeling efforts, we developed three probes using common analyte-responsive triggers for beta-galactosidase activity (PA-HD-Gal), nitroreductase activity (PA-HD-NTR), and hydrogen peroxide (PA-HD-H2O2). The performance of each probe (responsiveness, selectivity) was evaluated in vitro and in cellulo. To showcase the enhance properties afforded by PA-HD for in vivo photoacoustic imaging, we employed an Alzheimer’s disease model to detect H2O2. In particular, the photoacoustic signal at 735 nm in the brains of 5xFAD mice (a murine model of Alzheimer’s disease) increased by 1.72 ± 0.20-fold relative to background indicating the presence of oxidative stress, whereas the change in wildtype mice was negligible (1.02 ± 0.14). These results were confirmed via ratiometric calibration which was not possible using the parent HD platform.

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Cholesterol Alters Mitophagy By Impairing Optineurin Recruitment And Lysosomal Clearance In Alzheimer’s Disease

10.21203/rs.3.rs-69969/v3 ◽

2021 ◽

Author(s):

Vicente Roca-Agujetas ◽

Elisabet Barbero-Camps ◽

Cristina de Dios ◽

Petar Podlesniy ◽

Xenia Abadin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholesterol Homeostasis ◽

Critical Event ◽

Primary Neurons ◽

Cholesterol Levels ◽

Swedish Mutation ◽

Intracellular Cholesterol ◽

The Impact

Abstract Background: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer’s disease (AD) pathogenesis. Amyloid-beta (Ab) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Ab clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.Methods: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.Results: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Ab while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages. Conclusions: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

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Mechanistic Modeling of Soluble Aβ Dynamics and Target Engagement in the Brain by Anti-Aβ mAbs in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200302122307 ◽

2020 ◽

Vol 17 (4) ◽

pp. 393-406

Author(s):

Gregory Z. Ferl ◽

Reina N. Fuji ◽

Jasvinder K. Atwal ◽

Tony Sun ◽

Saroja Ramanujan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Mechanistic Modeling ◽

Model Parameters ◽

Target Engagement ◽

Binding Characteristics ◽

The Impact ◽

The Brain

Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer’s disease. Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics. Methods: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters. Results: Model-based estimates of in vivo affinity of the antibody to monomeric Aβ were qualitatively consistent with the previous data. Simulations of Aβ target engagement profiles captured observed mean and variance of clinical PK/PD data. Conclusion: This model is useful for comparing target engagement profiles of different anti-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aβ oligomer neutralization.

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Ganglion Cell Layer Thinning in Alzheimer’s Disease

Medicina ◽

10.3390/medicina56100553 ◽

2020 ◽

Vol 56 (10) ◽

pp. 553

Author(s):

Alicia López-de-Eguileta ◽

Andrea Cerveró ◽

Ainara Ruiz de Sabando ◽

Pascual Sánchez-Juan ◽

Alfonso Casado

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ganglion Cell Layer ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Preclinical Ad ◽

Future Direction ◽

The Impact

The main advantages of optical retinal imaging may allow researchers to achieve deeper analysis of retinal ganglion cells (GC) in vivo using optical coherence tomography (OCT). Using this device to elucidate the impact of Alzheimer’s disease (AD) on retinal health with the aim to identify a new AD biomarker, a large amount of studies has analyzed GC in different stages of the disease. Our review highlights recent knowledge into measuring retinal morphology in AD making distinctive between whether those studies included patients with clinical dementia stage or also mild cognitive impairment (MCI), which selection criteria were applied to diagnosed patients included, and which device of OCT was employed. Despite several differences, previous works found a significant thinning of GC layer in patients with AD and MCI. In the long term, an important future direction is to achieve a specific ocular biomarker with enough sensitivity to reveal preclinical AD disorder and to monitor progression.

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Cholesterol Alters Mitophagy by Impairing Optineurin Recruitment and Lysosomal Clearance in Alzheimer’s Disease

10.21203/rs.3.rs-69969/v2 ◽

2020 ◽

Author(s):

Vicente Roca-Agujetas ◽

Elisabet Barbero-Camps ◽

Cristina de Dios ◽

Petar Podlesniy ◽

Xenia Abadin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholesterol Homeostasis ◽

Critical Event ◽

Primary Neurons ◽

Cholesterol Levels ◽

Swedish Mutation ◽

Intracellular Cholesterol ◽

The Impact

Abstract Background: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer’s disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Aβ clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.Methods: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.Results: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Aβ while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages.Conclusions: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.

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Arterial Stiffening and Cerebrovascular Resistance in Cognitive Decline and Alzheimer’s Disease

Vascular Disease, Alzheimer's Disease, and Mild Cognitive Impairment ◽

10.1093/oso/9780190634230.003.0013 ◽

2020 ◽

pp. 274-301

Author(s):

Belinda Yew ◽

Anna Blanken ◽

Daniel A. Nation

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Vascular Dysfunction ◽

Vascular Cognitive Impairment ◽

Arterial Stiffening ◽

Small Vessels ◽

Cerebrovascular Resistance ◽

The Impact

The impact of vascular factors on cognitive decline and Alzheimer’s disease (AD) has been increasingly recognized. AD and vascular cognitive impairment exhibit significant overlap, individuals with vascular risk factors experience elevated risk for AD, and vascular mechanisms have been implicated in the genetic and pathological processes underlying development of AD. Arterial stiffening and cerebrovascular resistance have been identified as potential junctions through which vascular dysfunction promotes AD pathogenesis and cognitive decline. This chapter outlines the pathophysiology of arterial stiffening and cerebrovascular resistance, beginning in the aorta and small vessels of the brain, respectively. As these processes proliferate, cerebral circulation is disrupted, compromising capacity to meet neuronal metabolic needs and culminating in cognitive declines. An overview is provided of in vivo markers for arterial stiffening and cerebrovascular resistance, including methods employing pulse wave velocity, transcranial Doppler ultrasonography, and arterial spin labeling magnetic resonance imaging. Relevant research developments and their implications for conceptualization of vascular contributions to cognitive decline are discussed.

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