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1.
Molecular Imaging of Fluorinated Probes for Tau Protein and Amyloid-β Detection.
Yeo, SK, Shepelytskyi, Y, Grynko, V, Albert, MS
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Alzheimer's disease (AD) is the most common form of dementia and results in progressive neurodegeneration. The incidence rate of AD is increasing, creating a major public health issue. AD is characterized by neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein and senile plaques composed of amyloid-β (Aβ). Currently, a definitive diagnosis of AD is accomplished post-mortem. Thus, the use of molecular probes that are able to selectively bind to NFTs or Aβ can be valuable tools for the accurate and early diagnosis of AD. The aim of this review is to summarize and highlight fluorinated molecular probes that can be used for molecular imaging to detect either NFTs or Aβ. Specifically, fluorinated molecular probes used in conjunction with 19F MRI, PET, and fluorescence imaging will be explored.
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2.
Inflammation: A Major Target for Compounds to Control Alzheimer's Disease.
Maccioni, RB, Navarrete, LP, González, A, González-Canacer, A, Guzmán-Martínez, L, Cortés, N
Journal of Alzheimer's disease : JAD. 2020;(4):1199-1213
Abstract
Several hypotheses have been postulated to explain how Alzheimer's disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid-β peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmuno modulation theory, based on the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer's disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multi targeting compounds appear to provide a new pathway for Alzheimer's disease treatment.
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3.
Tryptophan metabolites modify brain Aβ peptide degradation: A role in Alzheimer's disease?
Maitre, M, Klein, C, Patte-Mensah, C, Mensah-Nyagan, AG
Progress in neurobiology. 2020;:101800
Abstract
Among several processes, a decrease in amyloid-beta (Aβ) peptide elimination is thought to be one of the major pathophysiological factors in Alzheimer's disease (AD). Neprilysin (NEP) is a key metalloproteinase controlling the degradation and clearance of Aβ peptides in the brain. NEP is induced by several pharmacological substances, amyloid deposits and somatostatin, but the physiological regulation of its expression remains unclear. This situation hampers the exploitation of NEP regulatory factors/mechanisms to develop effective strategies against Aβ peptide accumulation-induced brain toxicity. Based on recent data aimed at elucidating this major question, the present paper addresses and critically discusses the role of 5-hydroxyindole-acetic acid (5-HIAA) and kynurenic acid (KYNA) in the regulation of NEP activity/expression in the brain. Both 5-HIAA and KYNA are endogenous metabolites of tryptophan, an essential amino-acid obtained through diet and gut microbiome. By interacting with the aryl hydrocarbon receptor, various tryptophan metabolites modulate several metalloproteinases regulating brain Aβ peptide levels under normal and pathological conditions such as AD. In particular, interesting data reviewed here show that 5-HIAA and KYNA stimulate NEP activity/expression to prevent Aβ peptide-induced neurotoxicity. These data open promising perspectives for the development of tryptophan metabolite-based therapies against AD.
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4.
Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer's Disease.
Gião, T, Saavedra, J, Cotrina, E, Quintana, J, Llop, J, Arsequell, G, Cardoso, I
International journal of molecular sciences. 2020;(6)
Abstract
Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding to the retinol-binding protein), in these fluids. Still, this protein has managed to stay in the spotlight as it has been assigned new and varied functions. In this review, we cover knowledge on novel TTR functions and the cellular pathways involved, spanning from neuroprotection to vascular events, while emphasizing its involvement in Alzheimer's disease (AD). We describe details of TTR as an amyloid binding protein and discuss its interaction with the amyloid Aβ peptides, and the proposed mechanisms underlying TTR neuroprotection in AD. We also present the importance of translating advances in the knowledge of the TTR neuroprotective role into drug discovery strategies focused on TTR as a new target in AD therapeutics.
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5.
The Interplay between Diabetes and Alzheimer's Disease-In the Hunt for Biomarkers.
Kubis-Kubiak, A, Dyba, A, Piwowar, A
International journal of molecular sciences. 2020;(8)
Abstract
The brain is an organ in which energy metabolism occurs most intensively and glucose is an essential and dominant energy substrate. There have been many studies in recent years suggesting a close relationship between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) as they have many pathophysiological features in common. The condition of hyperglycemia exposes brain cells to the detrimental effects of glucose, increasing protein glycation and is the cause of different non-psychiatric complications. Numerous observational studies show that not only hyperglycemia but also blood glucose levels near lower fasting limits (72 to 99 mg/dL) increase the incidence of AD, regardless of whether T2DM will develop in the future. As the comorbidity of these diseases and earlier development of AD in T2DM sufferers exist, new AD biomarkers are being sought for etiopathogenetic changes associated with early neurodegenerative processes as a result of carbohydrate disorders. The S100B protein seem to be interesting in this respect as it may be a potential candidate, especially important in early diagnostics of these diseases, given that it plays a role in both carbohydrate metabolism disorders and neurodegenerative processes. It is therefore necessary to clarify the relationship between the concentration of the S100B protein and glucose and insulin levels. This paper draws attention to a valuable research objective that may in the future contribute to a better diagnosis of early neurodegenerative changes, in particular in subjects with T2DM and may be a good basis for planning experiments related to this issue as well as a more detailed explanation of the relationship between the neuropathological disturbances and changes of glucose and insulin concentrations in the brain.
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6.
Research Progress of Alzheimer's Disease Therapeutic Drugs: Based on Renin-Angiotensin System Axis.
Li, X, Xuan, W, Chen, D, Gao, H, Wang, G, Guo, Q, Wang, Y, Song, H, Cai, B
Journal of Alzheimer's disease : JAD. 2020;(4):1315-1338
Abstract
It is widely recognized that Alzheimer's disease (AD) has a complicate link to renin-angiotensin system (RAS). It is known that cerebrovascular disease has some connections with AD, but most of the studies are still conducted in parallel or independently. Although previous research came up with large number of hypotheses about the pathogenesis of AD, it does not include the mechanism of RAS-related regulation of AD. It has been found that many components of RAS have been changed in AD. For example, the multifunctional and high-efficiency vasoconstrictor Ang II and Ang III with similar effects are changed under the action of other RAS signal peptides; these signal peptides are believed to help improve nerve injury and cognitive function. These changes may lead to neuropathological changes of AD, and progressive defects of cognitive function, which are association with some hypotheses of AD. The role of RAS in AD gradually attracts our attention, and RAS deserved to be considered carefully in the pathogenesis of AD. This review discusses the mechanisms of RAS participating in the three current hypotheses of AD: neuroinflammation, oxidative stress and amyloid-β protein (Aβ) hypothesis, as well as the drugs that regulate RAS systems already in clinical or in clinical trials. It further demonstrates the importance of RAS in the pathogenesis of AD, not only because of its multiple aspects of participation, which may be accidental, but also because of the availability of RAS drugs, which can be reused as therapies of AD.
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7.
Resveratrol targeting tau proteins, amyloid-beta aggregations, and their adverse effects: An updated review.
Ashrafizadeh, M, Zarrabi, A, Najafi, M, Samarghandian, S, Mohammadinejad, R, Ahn, KS
Phytotherapy research : PTR. 2020;(11):2867-2888
Abstract
Resveratrol (Res) is a non-flavonoid compound with pharmacological actions such as antioxidant, antiinflammatory, hepatoprotective, antidiabetes, and antitumor. This plant-derived chemical has a long history usage in treatment of diseases. The excellent therapeutic impacts of Res and its capability in penetration into blood-brain barrier have made it an appropriate candidate in the treatment of neurological disorders (NDs). Tau protein aggregations and amyloid-beta (Aβ) deposits are responsible for the induction of NDs. A variety of studies have elucidated the role of these aggregations in NDs and the underlying molecular pathways in their development. In the present review, based on the recently published articles, we describe that how Res administration could inhibit amyloidogenic pathway and stimulate processes such as autophagy to degrade Aβ aggregations. Besides, we demonstrate that Res supplementation is beneficial in dephosphorylation of tau proteins and suppressing their aggregations. Then, we discuss molecular pathways and relate them to the treatment of NDs.
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8.
An overview of glutaminyl cyclase inhibitors for Alzheimer's disease.
Coimbra, JR, Sobral, PJ, Santos, AE, Moreira, PI, Salvador, JA
Future medicinal chemistry. 2019;(24):3179-3194
Abstract
A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have been discovered in Alzheimer's disease brains, including the pyroglutamate-Aβ (AβpE3). AβpE3 species are shown to be more neurotoxic when compared with the full-length Aβ peptide. Findings visibly suggest that glutaminyl cyclase (QC) catalyzed the generation of cerebral AβpE3, and therapeutic effects are achieved by reducing its activity. In recent years, efforts to effectively develop QC inhibitors have been pursued worldwide. The inhibitory activity of current QC inhibitors is mainly triggered by zinc-binding groups that coordinate Zn2+ ion in the active site and other common features. Herein, we summarized the current state of discovery and evolution of QC inhibitors as a potential Alzheimer's disease-modifying strategy.
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9.
Metal binding to the amyloid-β peptides in the presence of biomembranes: potential mechanisms of cell toxicity.
Wärmländer, SKTS, Österlund, N, Wallin, C, Wu, J, Luo, J, Tiiman, A, Jarvet, J, Gräslund, A
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2019;(8):1189-1196
Abstract
The amyloid-β (Aβ) peptides are key molecules in Alzheimer's disease (AD) pathology. They interact with cellular membranes, and can bind metal ions outside the membrane. Certain oligomeric Aβ aggregates are known to induce membrane perturbations and the structure of these oligomers-and their membrane-perturbing effects-can be modulated by metal ion binding. If the bound metal ions are redox active, as e.g., Cu and Fe ions are, they will generate harmful reactive oxygen species (ROS) just outside the membrane surface. Thus, the membrane damage incurred by toxic Aβ oligomers is likely aggravated when redox-active metal ions are present. The combined interactions between Aβ oligomers, metal ions, and biomembranes may be responsible for at least some of the neuronal death in AD patients.
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10.
Active-site environment of Cu bound amyloid β and amylin peptides.
Pal, I, Roy, M, Dey, SG
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2019;(8):1245-1259
Abstract
Alzheimer's disease (AD) and Type 2 Diabetes mellitus (T2Dm), two of the most common amyloidogenic diseases. They share a common pathological symptom, i.e., the formation of amyloid deposits comprised of amyloid β and amylin peptides, respectively. Autopsy of brains of AD-affected patients shows the presence of abnormally high concentrations of Cu in the deposited amyloid β plaques, while a significantly higher level of Cu is found in the serum of patients suffering from T2Dm. These invoke that Cu might play a crucial role in the onset of both AD and T2Dm. In fact, Cu is found to bind amyloid β as well as amylin relevant to AD and T2Dm, respectively. Cu-Aβ and Cu-amylin in their reduced states can generate partially reduced oxygen species (PROS) on reaction with O2 which leads to oxidative stress in the brain and in the pancreas, respectively. However, the pathway of O2 reduction is quite different for the two complexes. Moreover, the use of various spectroscopic techniques such as absorption, EPR, and CD involving native and site-directed mutants of the peptides show that their active-site environments are also dissimilar. Here, we have discussed the different aspects of Cu-Aβ and Cu-amylin complexes including their pH-dependent coordination environments and their reactivity towards O2 which may be responsible for the oxidative stress associated with the two diseases. This depicts the significance of the Cu bound peptide complexes in the context of AD and T2Dm. Graphic abstract.