Cytotoxic species in amyloid-associated diseases: Oligomers or mature fibrils.
Siddiqi Mohammad Khursheed,Malik Sadia,Majid Nabeela,Alam Parvez,Khan Rizwan Hasan
Advances in protein chemistry and structural biology
Amyloid diseases especially, Alzheimer's disease (AD), is characterized by an imbalance between the production and clearance of amyloid-β (Aβ) species. Amyloidogenic proteins or peptides can transform structurally from monomers into β-stranded fibrils via multiple oligomeric states. Among various amyloid species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of amyloid oligomers has been challenging due to their heterogeneous and metastable nature. Multiple techniques have recently helped in better understanding of oligomer's assembly details and structural properties. Moreover, some progress on elucidating the mechanisms of oligomer-triggered toxicity has been made. Based on the collection of current findings, there is growing consensus that control of toxic amyloid oligomers could be a valid approach to regulate amyloid-associated toxicity, which could advance development of new diagnostics and therapeutics for amyloid-related diseases. In this review, we have described the recent scenario of amyloid diseases with a great deal of information about the recent understanding of oligomers' assembly, structural properties, and toxicity. Also comprehensive details have been provided to differentiate the degree of toxicity associated with prefibrillar aggregates.
10.1016/bs.apcsb.2019.06.001
Structural studies of amyloid-β peptides: Unlocking the mechanism of aggregation and the associated toxicity.
Aleksis Rihards,Oleskovs Filips,Jaudzems Kristaps,Pahnke Jens,Biverstål Henrik
Biochimie
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. Formation of amyloid plaques consisting of amyloid-β peptides (Aβ) is one of the hallmarks of AD. Several lines of evidence have shown a correlation between the Aβ aggregation and the disease development. Extensive research has been conducted with the aim to reveal the structures of the neurotoxic Aβ aggregates. However, the exact structure of pathological aggregates and mechanism of the disease still remains elusive due to complexity of the occurring processes and instability of various disease-relevant Aβ species. In this article we review up-to-date structural knowledge about amyloid-β peptides, focusing on data acquired using solution and solid state NMR techniques. Furthermore, we discuss implications from these structural studies on the mechanisms of aggregation and neurotoxicity.
10.1016/j.biochi.2017.07.011
Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors.
Lee Shin Jung C,Nam Eunju,Lee Hyuck Jin,Savelieff Masha G,Lim Mi Hee
Chemical Society reviews
Alzheimer's disease (AD) is characterized by an imbalance between production and clearance of amyloid-β (Aβ) species. Aβ peptides can transform structurally from monomers into β-stranded fibrils via multiple oligomeric states. Among the various Aβ species, structured oligomers are proposed to be more toxic than fibrils; however, the identification of Aβ oligomers has been challenging due to their heterogeneous and metastable nature. Multiple techniques have recently helped us gain a better understanding of oligomers' assembly details and structural properties. Moreover, some progress on elucidating the mechanisms of oligomer-triggered toxicity has been made. Based on the collection of current findings, there is growing consensus that control of toxic Aβ oligomers could be a valid approach to regulate Aβ-associated toxicity, which could advance development of new diagnostics and therapeutics for amyloid-related diseases. In this review, we summarize the recent understanding of Aβ oligomers' assembly, structural properties, and toxicity, along with inhibitors against Aβ aggregation, including oligomerization.
10.1039/c6cs00731g
Using Models of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer's Disease.
BioMed research international
Autophagy is a conserved catabolic pathway that involves the engulfment of cytoplasmic components such as large protein aggregates and organelles that are delivered to the lysosome for degradation. This process is important in maintaining neuronal function and raises the possibility of a role for autophagy in neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent form of these diseases and is characterized by the accumulation of amyloid plaques in the brain which arise due to the misfolding and aggregation of toxic peptides, including amyloid beta (A). There is substantial evidence from both AD patients and animal models that autophagy is dysregulated in this disease. However, it remains to be determined whether this is protective or pathogenic as there is evidence that autophagy can act to promote the degradation as well as function in the generation of toxic A peptides. Understanding the molecular details of the extensive crosstalk that occurs between the autophagic and endolysosomal cellular pathways is essential for identifying the molecular details of amyloid toxicity. models that express the toxic proteins that aggregate in AD have been generated and have been shown to recapitulate hallmarks of the disease. Here we focus on what is known about the role of autophagy in amyloid toxicity in AD from mammalian models and how models can be used to further investigate AD pathogenesis.
10.1155/2018/5195416
Impact of a discordant helix on β-amyloid structure, aggregation ability and toxicity.
Chen Yi-Cheng
European biophysics journal : EBJ
According to amyloid cascade hypothesis, the deposit of amyloid-β (Aβ) peptide is the main cause of Alzheimer's disease (AD). The aggregation ability and toxicity of Aβ peptides are highly associated with the sequence and conformation. A discordant helix is a helical segment with a tendency to form a β-strand conformation and has been found in many amyloid-like proteins or peptides. In this review, we summarize the current knowledge of the properties of a Aβ discordant helix and its impact on the Aβ structure, aggregation ability and cytotoxicity. In an Aβ sequence, a discordant helical region located at residue 15-26 has been proposed. This discordant helix plays a vital role in Aβ conformation, aggregation ability and cytotoxicity. Any factors which can stabilize the structure of the discordant helix may lead to the prevention of aggregation and toxicity of Aβ. This makes the discordant helix an attractive target for the design of new drugs for the treatment of AD.
10.1007/s00249-017-1235-5
Amyloid toxicity in Alzheimer's disease.
Reiss Allison B,Arain Hirra A,Stecker Mark M,Siegart Nicolle M,Kasselman Lora J
Reviews in the neurosciences
A major feature of Alzheimer's disease (AD) pathology is the plaque composed of aggregated amyloid-β (Aβ) peptide. Although these plaques may have harmful properties, there is much evidence to implicate soluble oligomeric Aβ as the primary noxious form. Aβ oligomers can be generated both extracellularly and intracellularly. Aβ is toxic to neurons in a myriad of ways. It can cause pore formation resulting in the leakage of ions, disruption of cellular calcium balance, and loss of membrane potential. It can promote apoptosis, cause synaptic loss, and disrupt the cytoskeleton. Current treatments for AD are limited and palliative. Much research and effort is being devoted to reducing Aβ production as an approach to slowing or preventing the development of AD. Aβ formation results from the amyloidogenic cleavage of human amyloid precursor protein (APP). Reconfiguring this process to disfavor amyloid generation might be possible through the reduction of APP or inhibition of enzymes that convert the precursor protein to amyloid.
10.1515/revneuro-2017-0063
Membrane Damage Induced by Amyloid Beta and a Potential Link with Neuroinflammation.
Fernandez-Perez Eduardo J,Peters Christian,Aguayo Luis G
Current pharmaceutical design
It is well accepted that cortical and hippocampal synaptic densities are reduced in Alzheimer's disease (AD). These alterations in neuronal networking occur at the very onset of AD and may lead to the neuronal loss displayed in later stages of the disease, which is characterized by severe cognitive and behavioral impairments. Many studies suggest that amyloid-β (Aβ) oligomers are responsible for synaptic disconnections and neuronal death. The effects of Aβ in different brain regions are pleotropic, thus suggesting a common mechanism for toxicity. One potential site for this mechanism of toxicity is the neuronal membrane. It is recognized that Aβ can associate to the plasma membrane and induce the formation of pores after the interaction with lipids like GM1 and cholesterol, and proteins such as APP and NMDA receptors. After this early event, the membrane increases its permeability allowing the influx of small ions and larger molecules. Thus, one of the main toxic consequences of Aβ oligomer interaction with neurons is an increase in intracellular Ca(2+) concentration that causes alterations in ionic homeostasis. It has been proposed that Aβ perforates the membrane similarly to pore-forming toxins producing a series of effects that include synaptic failure and cell death. These actions of Aβ appear to be potentiated by neuroinflammation, which results in a series of effects that, when prolonged, will affect membrane integrity, pore formation and cellular homeostasis. Here, we will review the most recent data on Aβ actions at the membrane level and how its relationship with neuroinflammation could further potentiate brain impairment in AD. The notion of having drugs acting with dual inhibitory actions, inhibition of membrane damage and inflammation, could serve as a starting conceptual point for the development of new therapies for the disease.
Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer's disease.
Kam Tae-In,Gwon Youngdae,Jung Yong-Keun
Cellular and molecular life sciences : CMLS
Alzheimer's disease (AD) is the most common neurodegenerative disease. Although a major cause of AD is the accumulation of amyloid-β (Aβ) peptide that induces neuronal loss and cognitive impairments, our understanding of its neurotoxic mechanisms is limited. Recent studies have identified putative Aβ-binding receptors that mediate Aβ neurotoxicity in cells and models of AD. Once Aβ interacts with a receptor, a toxic signal is transduced into neurons, resulting in cellular defects including endoplasmic reticulum stress and mitochondrial dysfunction. In addition, Aβ can also be internalized into neurons through unidentified Aβ receptors and induces malfunction of subcellular organelles, which explains some part of Aβ neurotoxicity. Understanding the neurotoxic signaling initiated by Aβ-receptor binding and cellular defects provide insight into new therapeutic windows for AD. In the present review, we summarize the findings on Aβ-binding receptors and the neurotoxicity of oligomeric Aβ.
10.1007/s00018-014-1706-0
Nrf2 regulates neurogenesis and protects neural progenitor cells against Aβ toxicity.
Kärkkäinen Virve,Pomeshchik Yuriy,Savchenko Ekaterina,Dhungana Hiramani,Kurronen Antti,Lehtonen Sarka,Naumenko Nikolay,Tavi Pasi,Levonen Anna-Liisa,Yamamoto Masayuki,Malm Tarja,Magga Johanna,Kanninen Katja M,Koistinaho Jari
Stem cells (Dayton, Ohio)
Neural stem/progenitor cells (NPCs) proliferate and produce new neurons in neurogenic areas throughout the lifetime. While these cells represent potential therapeutic treatment of neurodegenerative diseases, regulation of neurogenesis is not completely understood. We show that deficiency of nuclear factor erythroid 2-related factor (Nrf2), a transcription factor induced in response to oxidative stress, prevents the ischemia-induced increase in newborn neurons in the subgranular zone of the dentate gyrus. Consistent with this finding, the growth of NPC neurospheres was increased by lentivirus-mediated overexpression of Nrf2 gene or by treatment with pyrrolidine dithiocarbamate (PDTC), an Nrf2 activating compound. Also, neuronal differentiation of NPCs was increased by Nrf2 overexpression or PDTC treatment but reduced by Nrf2 deficiency. To investigate the impact of Nrf2 on NPCs in Alzheimer's disease (AD), we treated NPCs with amyloid beta (Aβ), a toxic peptide associated with neurodegeneration and cognitive abnormalities in AD. We found that Aβ1-42-induced toxicity and reduction in neurosphere proliferation were prevented by Nrf2 overexpression, while Nrf2 deficiency enhanced the Aβ1-42-induced reduction of neuronal differentiation. On the other hand, Aβ1-40 had no effect on neurosphere proliferation in wt NPCs but increased the proliferation of Nrf2 overexpressing neurospheres and reduced it in Nrf2-deficient neurospheres. These results suggest that Nrf2 is essential for neuronal differentiation of NPCs, regulates injury-induced neurogenesis and provides protection against Aβ-induced NPC toxicity.
10.1002/stem.1666
Spatial Dynamics of Vascular and Biochemical Injury in Rat Hippocampus Following Striatal Injury and Aβ Toxicity.
Amtul Zareen,Frías Carmen,Randhawa Jasmine,Hill David J,Arany Edith J
Molecular neurobiology
The hippocampus, a brain region vital for memory and learning, is sensitive to the damage caused by ischemic/hypoxic stroke and is one of the main regions affected by Alzheimer's disease. The pathological changes that might occur in the hippocampus and its connections, because of cerebral injury in a distant brain region, such as the striatum, have not been examined. Therefore, in the present study, we evaluated the combined effects of endothelin-1-induced ischemia (ET1) in the striatum and β-amyloid (Aβ) toxicity on hippocampal pathogenesis, dictated by the anatomical and functional intra- and inter-regional hippocampal connections to the striatum. The hippocampal pathogenesis induced by Aβ or ET1 alone was not severe enough to significantly affect the entire circuit of the hippocampal network. However, the combination of the two pathological states (ET1 + Aβ) led to an exacerbated increase in neuroinflammation, deposition of the amyloid precursor protein (APP) fragments with the associated appearance of degenerating cells, and blood-brain-barrier disruption. This was observed mainly in the hippocampal formation (CA2 and CA3 regions), the dentate gyrus as well as distinct regions with synaptic links to the hippocampus such as entorhinal cortex, thalamus, and basal forebrain. In addition, ET1 + Aβ-treated rats also demonstrated protracted loss of AQP4 depolarization, dissolution of β-dystroglycan, and basement membrane laminin with associated IgG and dysferlin leakage. Spatial dynamics of hippocampal injury in ET1 + Aβ rats may provide a valuable model to study new targets for clinical therapeutic applications, specifically when areas remotely connected to hippocampus are damaged.
10.1007/s12035-018-1225-3
Neuronal susceptibility to beta-amyloid toxicity and ischemic injury involves histone deacetylase-2 regulation of endophilin-B1.
Wang David B,Kinoshita Chizuru,Kinoshita Yoshito,Sopher Bryce L,Uo Takuma,Lee Rona J,Kim Joon Kyu,Murphy Sean P,Dirk Keene C,Garden Gwenn A,Morrison Richard S
Brain pathology (Zurich, Switzerland)
Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron-specific splice isoforms of Endophilin-B1 (Endo-B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo-B1 expression. HDAC2 knockdown or knockout enhances expression of Endo-B1. Conversely, HDAC2 overexpression decreases Endo-B1 expression. We also demonstrate that neurons exposed to beta-amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase-3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo-B1 shRNA and in Endo-B1-null neurons, suggesting that HDAC2-induced neurotoxicity is mediated through suppression of Endo-B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo-B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo-B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.
10.1111/bpa.12647