Trichostatin A ameliorates Alzheimer’s disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice

Abstract Background Alzheimer’s disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. Methods Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS. Results TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers. Conclusions These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.

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The inhibition of cellular toxicity of amyloid-β by dissociated transthyretin

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013440 ◽

2020 ◽

Vol 295 (41) ◽

pp. 14015-14024 ◽

Cited By ~ 1

Author(s):

Qin Cao ◽

Daniel H. Anderson ◽

Wilson Y. Liang ◽

Joshua Chou ◽

Lorena Saelices

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protective Effect ◽

Amyloid Β ◽

Inhibitory Effect ◽

Aβ Oligomers ◽

Cellular Toxicity ◽

Computational Docking

The protective effect of transthyretin (TTR) on cellular toxicity of β-amyloid (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aβ, a protein associated with Alzheimer's disease. TTR binds Aβ, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ-binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aβ oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

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Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21165858 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5858 ◽

Cited By ~ 3

Author(s):

Md. Sahab Uddin ◽

Md. Tanvir Kabir ◽

Md. Sohanur Rahman ◽

Tapan Behl ◽

Philippe Jeandet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Clinical Symptoms ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Amyloid Β ◽

Aβ Oligomers ◽

Aβ Aggregation ◽

Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

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Influence of Woodsmoke Exposure on Molecular Mechanisms Underlying Alzheimer’s Disease: Existing Literature and Gaps in Our Understanding

Epigenetics Insights ◽

10.1177/2516865720954873 ◽

2020 ◽

Vol 13 ◽

pp. 251686572095487

Author(s):

Adam Schuller ◽

Luke Montrose

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Air Pollution ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Ambient Air ◽

The United States ◽

Ambient Air Pollution ◽

Current Status

Woodsmoke poses a significant health risk as a growing component of ambient air pollution in the United States. While there is a long history of association between woodsmoke exposure and diseases of the respiratory, circulatory, and cardiovascular systems, recent evidence has linked woodsmoke exposure to cognitive dysfunction, including Alzheimer’s disease dementia. Alzheimer’s disease is a progressive neurodegenerative disorder with largely idiopathic origins and no known cure. Here, we explore the growing body of literature which relates woodsmoke-generated and ambient air pollution particulate matter exposure to Alzheimer’s disease (AD) onset or exacerbation, in the context of an inflammation-centric view of AD. Epigenetic modifications, specifically changes in DNA methylation patterns, are well documented following woodsmoke exposure and have been shown to influence disease-favoring inflammatory cascades, induce oxidative stress, and modulate the immune response in vitro, in vivo, and in humans following exposure to air pollution. Though the current status of the literature does not allow us to draw definitive conclusions linking these events, this review highlights the need for additional work to fill gaps in our understanding of the directionality, causality, and susceptibility throughout the life course.

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Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

Biochemical Society Transactions ◽

10.1042/bst0390819 ◽

2011 ◽

Vol 39 (3) ◽

pp. 819-822 ◽

Cited By ~ 18

Author(s):

Ana M. Mata ◽

María Berrocal ◽

M. Rosario Sepúlveda

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plasma Membrane ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Senile Plaques ◽

Amyloid Β ◽

Inhibitory Effect ◽

Amyloid Β Peptide ◽

Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

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Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Antioxidants ◽

10.3390/antiox10091353 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1353

Author(s):

Francesca Romana Buccellato ◽

Marianna D’Anca ◽

Chiara Fenoglio ◽

Elio Scarpini ◽

Daniela Galimberti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Oxidative Damage ◽

Molecular Mechanisms ◽

Biomarker Discovery ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Antioxidant Defenses ◽

Ageing Population

Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

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Plant sphingolipids promote extracellular vesicle release and alleviate amyloid-β pathologies in a mouse model of Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-019-53394-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Kohei Yuyama ◽

Kaori Takahashi ◽

Seigo Usuki ◽

Daisuke Mikami ◽

Hui Sun ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Neuronal Cultures ◽

Amyloid Β Protein ◽

Neuronal Marker ◽

Enhanced Production ◽

Model Of Alzheimer’S Disease ◽

Aβ Clearance

AbstractThe accumulation of amyloid-β protein (Aβ) in brain is linked to the early pathogenesis of Alzheimer’s disease (AD). We previously reported that neuron-derived exosomes promote Aβ clearance in the brains of amyloid precursor protein transgenic mice and that exosome production is modulated by ceramide metabolism. Here, we demonstrate that plant ceramides derived from Amorphophallus konjac, as well as animal-derived ceramides, enhanced production of extracellular vesicles (EVs) in neuronal cultures. Oral administration of plant glucosylceramide (GlcCer) to APP overexpressing mice markedly reduced Aβ levels and plaque burdens and improved cognition in a Y-maze learning task. Moreover, there were substantial increases in the neuronal marker NCAM-1, L1CAM, and Aβ in EVs isolated from serum and brain tissues of the GlcCer-treated AD model mice. Our data showing that plant ceramides prevent Aβ accumulation by promoting EVs-dependent Aβ clearance in vitro and in vivo provide evidence for a protective role of plant ceramides in AD. Plant ceramides might thus be used as functional food materials to ameliorate AD pathology.

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CNI-1493 inhibits Aβ production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

Journal of Experimental Medicine ◽

10.1084/jem.20060467 ◽

2008 ◽

Vol 205 (7) ◽

pp. 1593-1599 ◽

Cited By ~ 14

Author(s):

Michael Bacher ◽

Richard Dodel ◽

Bayan Aljabari ◽

Kathy Keyvani ◽

Philippe Marambaud ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Performance ◽

Amyloid Β ◽

Amyloid Plaque ◽

Amyloid Β Protein ◽

Aβ Oligomers ◽

App Processing ◽

Model Of Alzheimer’S Disease

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid β protein (Aβ) peptide “oligomers” and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Aβ assembly and protects neuronal cells from the toxic effect of soluble Aβ oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Aβ deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Aβ accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.

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Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease

10.1101/2020.08.20.260166 ◽

2020 ◽

Author(s):

Sourav Samanta ◽

Kolla Rajasekhar ◽

Madhu Ramesh ◽

N. Arul Murugan ◽

Shadab Alam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Deficits ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Salt Bridges ◽

Amyloid Burden ◽

Amyloid Toxicity ◽

Model Of Alzheimer’S Disease

ABSTRACTAlzheimer’s disease (AD) is a major neurodegenerative disorder and the leading cause of dementia worldwide. Predominantly, misfolding and aggregation of amyloid-β (Aβ) peptides associated with multifaceted toxicity is the neuropathological hallmark of AD pathogenesis and thus, primary therapeutic target to ameliorate neuronal toxicity and cognitive deficits. Herein, we report the design, synthesis and evaluation of small molecule inhibitors with naphthalene monoimide scaffold to ameliorate in vitro and in vivo amyloid induced neurotoxicity. The detailed studies established TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. The in silico studies showed disruption of salt bridges and intermolecular hydrogen bonding interactions within Aβ42 fibrils by the interaction of TGR63, causing destabilization of Aβ42 assembly. Remarkably, TGR63 treatment showed a significant reduction in cortical and hippocampal amyloid burden in the progressive stages of APP/PS1 AD mice brain. Various behavioral tests demonstrated rescued cognitive deficits. The excellent biocompatibility, BBB permeability and therapeutic efficacy to reduce amyloid burden make TGR63 a promising candidate for the treatment of AD.

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Rational design of a conformation-specific antibody for the quantification of Aβ oligomers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1919464117 ◽

2020 ◽

Vol 117 (24) ◽

pp. 13509-13518 ◽

Cited By ~ 8

Author(s):

Francesco A. Aprile ◽

Pietro Sormanni ◽

Marina Podpolny ◽

Shianne Chhangur ◽

Lisa-Maria Needham ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Misfolding ◽

Rational Design ◽

Design Method ◽

Amyloid Β ◽

In Vitro Assays ◽

Aβ Oligomers ◽

Detection And Quantification

Protein misfolding and aggregation is the hallmark of numerous human disorders, including Alzheimer’s disease. This process involves the formation of transient and heterogeneous soluble oligomers, some of which are highly cytotoxic. A major challenge for the development of effective diagnostic and therapeutic tools is thus the detection and quantification of these elusive oligomers. Here, to address this problem, we develop a two-step rational design method for the discovery of oligomer-specific antibodies. The first step consists of an “antigen scanning” phase in which an initial panel of antibodies is designed to bind different epitopes covering the entire sequence of a target protein. This procedure enables the determination through in vitro assays of the regions exposed in the oligomers but not in the fibrillar deposits. The second step involves an “epitope mining” phase, in which a second panel of antibodies is designed to specifically target the regions identified during the scanning step. We illustrate this method in the case of the amyloid β (Aβ) peptide, whose oligomers are associated with Alzheimer’s disease. Our results show that this approach enables the accurate detection and quantification of Aβ oligomers in vitro, and inCaenorhabditis elegansand mouse hippocampal tissues.

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Deconstructing Alzheimer’s Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?

International Journal of Molecular Sciences ◽

10.3390/ijms22168769 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8769

Author(s):

Anaïs Vignon ◽

Lucie Salvador-Prince ◽

Sylvain Lehmann ◽

Véronique Perrier ◽

Joan Torrent

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Amyloid Β ◽

Experimental Models ◽

Tau Proteins ◽

Human Pathology ◽

Set Up

Discovered more than a century ago, Alzheimer’s disease (AD) is not only still present in our societies but has also become the most common dementia, with 50 million people worldwide affected by the disease. This number is expected to double in the next generation, and no cure is currently available to slow down or stop the disease progression. Recently, some advances were made due to the approval of the aducanumab treatment by the American Food and Drug Administration. The etiology of this human-specific disease remains poorly understood, and the mechanisms of its development have not been completely clarified. Several hypotheses concerning the molecular mechanisms of AD have been proposed, but the existing studies focus primarily on the two main markers of the disease: the amyloid β peptides, whose aggregation in the brain generates amyloid plaques, and the abnormally phosphorylated tau proteins, which are responsible for neurofibrillary tangles. These protein aggregates induce neuroinflammation and neurodegeneration, which, in turn, lead to cognitive and behavioral deficits. The challenge is, therefore, to create models that best reproduce this pathology. This review aims at gathering the different existing AD models developed in vitro, in cellulo, and in vivo. Many models have already been set up, but it is necessary to identify the most relevant ones for our investigations. The purpose of the review is to help researchers to identify the most pertinent disease models, from the most often used to the most recently generated and from simple to complex, explaining their specificities and giving concrete examples.

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