Toxic Tau Oligomers Modulated by Novel Curcumin Derivatives

The pathological aggregation and accumulation of tau, a microtubule-associated protein, is a common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated that the soluble and hydrophobic tau oligomers are highly toxic in vitro due to their capacity towards seeding tau misfolding, thereby propagating the tau pathology seen across different neurodegenerative diseases. Modulating the aggregation state of tau oligomers through the use of small molecules could be a useful therapeutic strategy to target their toxicity, regardless of other factors involved in their formation. In this study, we screened and tested a small library of newly synthesized curcumin derivatives against preformed recombinant tau oligomers. Our results show that the curcumin derivatives affect and modulate the tau oligomer aggregation pathways, converting to a more aggregated non-toxic state as assessed in the human neuroblastoma SH-SY5Y cell line and primary cortical neuron cultures. These results provide insight into tau aggregation and may become a basis for the discovery of new therapeutic agents, as well as advance the diagnostic field for the detection of toxic tau oligomers

Amyloid prions in fungi

ABSTRACT Prions are infectious protein polymers that have been found to cause fatal diseases in mammals. Prions have also been identified in fungi (yeast and filamentous fungi), where they behave as cytoplasmic non-Mendelian genetic elements. Fungal prions correspond in most cases to fibrillary β-sheet-rich protein aggregates termed amyloids. Fungal prion models and, in particular, yeast prions were instrumental in the description of fundamental aspects of prion structure and propagation. These models established the “protein-only” nature of prions, the physical basis of strain variation, and the role of a variety of chaperones in prion propagation and amyloid aggregate handling. Yeast and fungal prions do not necessarily correspond to harmful entities but can have adaptive roles in these organisms.</jats:p

Anti-Inflammatory activity of a polyphenolic extract from Arabidopsis thaliana in in vitro and in vivo models of Alzheimer's Disease

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

The Formyl Peptide Receptor 2 Regulates Microglial Phenotype Through Immunometabolism: Implications for Alzheimer’s Disease

Microglia are key players in the pathology of Alzheimer’s disease (AD), driving chronic inflammation, oxidative stress, and the altered metabolism seen in the brains of patients. With clinical trials continuing to fail, new approaches towards drug development are critical. Strategies to reduce microglial activation may therefore be a viable therapeutic approach to tackling AD. Formyl peptide receptor 2 (Fpr2), which drives peripheral inflammatory resolution, is expressed in microglia. However, its functional role in neuroinflammation is unclear. This thesis provides evidence to support the peripheral findings of Fpr2 stimulation, wherein it may also hold promise for exploitation as a therapeutic for neurodegenerative disorders, including AD. We also highlight novel findings surrounding the modulation of both oxidative stress and microglial metabolism associated with Fpr2 activation. Under inflammatory conditions, we report that selective agonists for Fpr2 modulate the microglial inflammatory response, actively shifting from a pro-inflammatory to a pro-resolving phenotype, emphasised by the reduction of pro-inflammatory cytokines and concomitant increases in both pro-resolving cytokines and phagocytosis. Metabolic shifting away from glycolysis was also observed for pro-resolving microglia. Moreover, we describe for the first time that Fpr2 completely reverses reactive oxygen species (ROS) production from the mitochondria and NADPH oxidase enzymes following an inflammatory stimulus. We also highlight that the toxic oligomeric amyloid (oAβ) facilitates microglial ROS production and subsequent metabolic changes without triggering an inflammatory response. oAβ facilitated NADPH oxidase activation, which in turn resulted in the activation of glucose 6-phosphate dehydrogenase (G6PD), the rate limiting step for the pentose phosphate pathway. This metabolic pathway is responsible for producing NADPH, which in turn NADPH oxidases exploit for further ROS production. These changes resulted in noticeable reductions in both microglial glycolysis and oxidative phosphorylation. We present data underlining that Fpr2/3 stimulation reverses oAβ-induced ROS production, with a resultant reduction in G6PD activity and the return of homeostatic glycolysis. These oAβ-induced microglial changes triggered the apoptosis of SH-SY5Y cells in co-culture with BV-2 microglia. However, supporting our interest in Fpr2/3 for therapeutic approaches to neurodegenerative diseases, post-treatment with a select agonist for the receptor successfully prevented apoptosis of these neuronal like SH-SY5Y cells. This original data unveils novel functions of Fpr2/3 in the central nervous system (CNS), supplementing the well-established pro-resolving functions the receptor facilitates within the periphery. The combination of pro-resolving, anti-oxidative, immunometabolic and anti-apoptotic functions of Fpr2/3 support the exploitation of this receptor for therapeutic research into multiple different CNS disorders, including AD

Targeting neuroinflammation in Alzheimer’s disease

Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer’s disease (AD) accounts for approximately 60%–80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder

The relationship between amyloid structure and cytotoxicity

Self-assembly of proteins and peptides into amyloid structures has been the subject of intense and focused research due to their association with neurodegenerative, age-related human diseases and transmissible prion diseases in humans and mammals. Of the disease associated amyloid assemblies, a diverse array of species, ranging from small oligomeric assembly intermediates to fibrillar structures, have been shown to have toxic potential. Equally, a range of species formed by the same disease associated amyloid sequences have been found to be relatively benign under comparable monomer equivalent concentrations and conditions. In recent years, an increasing number of functional amyloid systems have also been found. These developments show that not all amyloid structures are generically toxic to cells. Given these observations, it is important to understand why amyloid structures may encode such varied toxic potential despite sharing a common core molecular architecture. Here, we discuss possible links between different aspects of amyloidogenic structures and assembly mechanisms with their varied functional effects. We propose testable hypotheses for the relationship between amyloid structure and its toxic potential in the context of recent reports on amyloid sequence, structure, and toxicity relationships

Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2'-pyridyl)benzimidazole Ligands

The effect of analogue Pd(II)-, Pt(II)-, and Au(III) compounds featuring 2-(2'-pyridyl)benzimidazole on the aggregation propensity of amyloid-like peptides derived from Aβ and from the C-terminal domain of nucleophosmin 1 was investigated. Kinetic profiles of aggregation were evaluated using thioflavin binding assays, whereas the interactions of the compounds with the peptides were studied by UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. The results indicate that the compounds modulate the aggregation of the investigated peptides using different mechanisms, suggesting that the reactivity of the metal center and the physicochemical properties of the metals (rather than those of the ligands and the geometry of the metal compounds) play a crucial role in determining the anti-aggregation properties

Alzheimer's disease pathology and the unfolded protein response : Prospective pathways and therapeutic targets

The authors would like to thank Alzheimer's Research UK (Grant refs: ARUK-PPG2014A-21 and ARUK-NSG2015-1 to BP and DK) who have provided support for relevant projects leading to this review.Peer reviewedPostprin