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Alternative hypotheses related to Alzheimer's disease.
Cubinkova, V, Valachova, B, Uhrinova, I, Brezovakova, V, Smolek, T, Jadhav, S, Zilka, N
Bratislavske lekarske listy. 2018;(4):210-216
Abstract
Alzheimer's disease represents the most common form of dementia and belongs to the group of neurodegenerative disorders characterized by progressive loss of neurons in the central nervous system. In the pathogenesis of Alzheimer's disease several etiologic and pathogenic factors exist, which lead to the dysfunction of neurotransmitter systems and consequent cognitive decline. Last three decades have delivered a crucial progress leading to better understanding of Alzheimer's disease, however, the exact mechanisms of pathology remain unclear. In this review, we summarize some hypotheses such as amyloid and tau hypotheses, inflammatory processes, prion-like hypothesis, the hypothesis of oxidative stress, vascular and cholesterol hypothesis, the hypothesis of metal accumulation in the brain, cell cycle hypothesis, the hypothesis of impaired insulin signalization and another, which were proposed to explain the pathogenesis of this severe disorder (Ref. 115).
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Catalytic Mechanism of Amyloid-β Peptide Degradation by Insulin Degrading Enzyme: Insights from Quantum Mechanics and Molecular Mechanics Style Møller-Plesset Second Order Perturbation Theory Calculation.
Lai, R, Tang, WJ, Li, H
Journal of chemical information and modeling. 2018;(9):1926-1934
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Abstract
Insulin degrading enzyme (IDE), a metalloprotease that degrades amyloid-β (Aβ) peptides and insulin, is associated with Alzheimer's disease and diabetes. The mechanism of IDE catalyzed degrading of Aβ peptides, which is of fundamental importance in the design of therapeutic methods for Alzheimer's disease, has not been fully understood. In this work, combined quantum mechanics and molecular mechanics (QM/MM) style Møller-Plesset second order perturbation theory (MP2) geometry optimization calculations are performed to investigate the catalytic mechanism of the Aβ40 Phe19-Phe20 peptide bond cleavage by human IDE. The analyses using QM/MM MP2 optimization suggest that a neutral water molecule is at the active site of the enzyme-substrate (ES) complex. The water molecule is in hydrogen bonding with the nearby anionic Glu111 of IDE but not directly bound to the catalytic Zn ion. This is confirmed by QM/MM DFTB3 molecular dynamics simulation. Our studies also reveal that the hydrolysis of the Aβ40 Phe19-Phe20 peptide bond by IDE consists of four key steps. The neutral water is first activated by moving toward and binding to the Zn ion. A gem-diol intermediate is then formed by the activated neutral water molecule attacking the C atom of the Phe19-Phe20 peptide bond. The next is the protonation of the N atom of Phe19-Phe20 peptide bond to form an intermediate with an elongated C-N bond. The final step is the breaking of the Phe19-Phe20 C-N bond. The final step is the rate-determining step with a calculated Gibbs free energy of activation of 17.34 kcal/mol, in good agreement with the experimental value 16.7 kcal/mol. This mechanism provides the basis for the design of biochemical methods to modulate the activity of IDE in humans.
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Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study.
Timmers, M, Streffer, JR, Russu, A, Tominaga, Y, Shimizu, H, Shiraishi, A, Tatikola, K, Smekens, P, Börjesson-Hanson, A, Andreasen, N, et al
Alzheimer's research & therapy. 2018;(1):85
Abstract
BACKGROUND β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. METHODS In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6-8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1-40 [Aβ1-40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. RESULTS In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ1-40 levels from baseline at day 28 in both the 10-mg (67-68%) and 50-mg (87-90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were - 69.37 (- 72.25; - 61.50) and - 92.74 (- 100.08; - 85.39), and for Japanese with preclinical AD, they were - 62.48 (- 78.32; - 46.64) and - 80.81 (- 96.13; - 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60-70% and 90% Aβ1-40 reductions, respectively. The trend of the reduction was similar across the Aβ1-37, Aβ1-38, and Aβ1-42 fragments in both atabecestat dose groups, consistent with Aβ1-40. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. CONCLUSIONS JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ1-40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults. TRIAL REGISTRATION ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.
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Amyloid-β/Drug Interactions from Computer Simulations and Cell-Based Assays.
Nguyen, PH, Del Castillo-Frias, MP, Berthoumieux, O, Faller, P, Doig, AJ, Derreumaux, P
Journal of Alzheimer's disease : JAD. 2018;(s1):S659-S672
Abstract
Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer's disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40/Aβ42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.
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Metal Ion Effects on Aβ and Tau Aggregation.
Kim, AC, Lim, S, Kim, YK
International journal of molecular sciences. 2018;(1)
Abstract
Amyloid and tau aggregation are implicated in manifold neurodegenerative diseases and serve as two signature pathological hallmarks in Alzheimer's disease (AD). Though aging is considered as a prominent risk factor for AD pathogenesis, substantial evidence suggests that an imbalance of essential biometal ions in the body and exposure to certain metal ions in the environment can potentially induce alterations to AD pathology. Despite their physiological importance in various intracellular processes, biometal ions, when present in excessive or deficient amounts, can serve as a mediating factor for neurotoxicity. Recent studies have also demonstrated the contribution of metal ions found in the environment on mediating AD pathogenesis. In this regard, the neuropathological features associated with biometal ion dyshomeostasis and environmental metal ion exposure have prompted widespread interest by multiple research groups. In this review, we discuss and elaborate on findings from previous studies detailing the possible role of both endogenous and exogenous metal ions specifically on amyloid and tau pathology in AD.
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Commentary: Fatty acids and Alzheimer's disease: evidence on cognition and cortical β-amyloid from secondary analyses of the Multidomain Alzheimer Preventive Trial.
Hooper, C, Vellas, B
The journal of prevention of Alzheimer's disease. 2018;(3):168-170
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Elucidating the Structures of Amyloid Oligomers with Macrocyclic β-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases.
Kreutzer, AG, Nowick, JS
Accounts of chemical research. 2018;(3):706-718
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Abstract
In the more than a century since its identification, Alzheimer's disease has become the archetype of amyloid diseases. The first glimpses of the chemical basis of Alzheimer's disease began with the identification of "amyloid" plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with "cross-β" structure in 1968. Further efforts led to the discovery of the β-amyloid peptide, Aβ, as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils. At this point, a three-decade-long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer's disease. Along the way, an alternative model began to emerge in which small aggregates of Aβ, called "oligomers", rather than fibrils, are the culprits that lead to neurodegeneration in Alzheimer's disease. This Account describes what is known about the structures of the fibrils and details our research group's efforts to understand the structural, biophysical, and biological properties of the oligomers in amyloid diseases. β-Sheets are the building blocks of amyloid fibrils and oligomers. Amyloid fibrils generally consist of extended networks of parallel β-sheets. Amyloid oligomers appear to be more compact enclosed structures, some of which are thought to be composed of antiparallel β-sheets comprising β-hairpins. β-Hairpins are special because their twisted shape, hydrophobic surfaces, and exposed hydrogen-bonding edges impart a unique propensity to form compact assemblies. Our laboratory has developed macrocyclic β-sheets that are designed to mimic β-hairpins formed by amyloidogenic peptides and proteins. The β-hairpin mimics contain two β-strand peptide fragments linked together at their N- and C-termini by two δ-linked ornithine turn mimics to create a macrocycle. An N-methyl group is installed on one of the β-strands to prevent uncontrolled aggregation. These design features facilitate crystallization of the β-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form. During the past few years, our laboratory has elucidated the X-ray crystallographic structures of oligomers formed by β-hairpin mimics derived from Aβ, α-synuclein, and β2-microglobulin. Out of these three amyloidogenic peptides and proteins, the Aβ β-hairpin mimics have provided the most insight into amyloid oligomers. Our studies have revealed a previously undiscovered mode of self-assembly, whereby three Aβ β-hairpin mimics assemble to form a triangular trimer. The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers. Some of the dodecamers pack in the crystal lattice to form annular porelike assemblies. Some of the β-hairpin mimics and triangular trimers assemble in solution to form oligomers that recapitulate the crystallographically observed oligomers. These oligomers exhibit toxicity toward neuronally derived cells, recapitulating the toxicity of the oligomers formed by full-length amyloidogenic peptides and proteins. These findings are significant, because they address a gap in understanding the molecular basis of amyloid diseases. We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer's disease, Parkinson's disease, and other amyloid diseases.
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Epitomic Characterization of the Specificity of the Anti-Amyloid Aβ Monoclonal Antibodies 6E10 and 4G8.
Baghallab, I, Reyes-Ruiz, JM, Abulnaja, K, Huwait, E, Glabe, C
Journal of Alzheimer's disease : JAD. 2018;(3):1235-1244
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Abstract
The monoclonal antibodies 6E10 and 4G8 are among the first anti-amyloid monoclonal antibodies against Aβ and the most widely used antibodies in Alzheimer's disease research. Although the epitopes for 6E10 and 4G8 have been reported to correspond to residues 1-16 and 17-24, a more recent high-resolution mapping approach indicates that 6E10 maps to residues 4-10 while 4G8 maps to residues 18-23. To characterize the binding specificity of both antibodies in greater detail, we used immunoselection of random sequences from phage display library followed by deep sequencing and analysis of resulting patterns from thousands of immunoselected sequences. We found that the minimum sequence required for 6E10 binding is R-x-D with over half (53%) of the immunoselected sequences conforming to this pattern. The vast majority of these sequences contain an H at position x (R-H-D), corresponding to residues 5-7 of the Aβ target sequences, but Y is also permitted at this position in a minority of sequences. For 4G8 we found that the most frequent pattern is F-x-A contained in approximately 30% of the sequences, followed by F-A, L-x(3)-A, L-x-F, and F-F each accounting for approximately 18% of the sequences. The F-x-A motif also occurs in islet amyloid poly peptide which may explain why 4G8 also recognizes amyloid fibrils of this peptide. Immunoselection of random sequences and deep sequencing may also be a facile and efficient means of determining residues critical for antibody binding and validating the specificity of monoclonal antibodies and polyclonal antisera.
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Unraveling the Burden of Iron in Neurodegeneration: Intersections with Amyloid Beta Peptide Pathology.
Uranga, RM, Salvador, GA
Oxidative medicine and cellular longevity. 2018;:2850341
Abstract
Iron overload is a hallmark of many neurodegenerative processes such as Alzheimer's, Parkinson's, and Huntington's diseases. Unbound iron accumulated as a consequence of brain aging is highly reactive with water and oxygen and produces reactive oxygen species (ROS) or free radicals. ROS are toxic compounds able to damage cell membranes, DNA, and mitochondria. Which are the mechanisms involved in neuronal iron homeostasis and in neuronal response to iron-induced oxidative stress constitutes a cutting-edge topic in metalloneurobiology. Increasing our knowledge about the underlying mechanisms that operate in iron accumulation and their consequences would shed light on the comprehension of the molecular events that participate in the pathophysiology of the abovementioned neurodegenerative diseases. In this review, current evidences about iron accumulation in the brain, the signaling mechanisms triggered by metal overload, as well as the interaction between amyloid β (Aβ) and iron, will be summarized.
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Allosteric sodium binding cavity in GPR3: a novel player in modulation of Aβ production.
Capaldi, S, Suku, E, Antolini, M, Di Giacobbe, M, Giorgetti, A, Buffelli, M
Scientific reports. 2018;(1):11102
Abstract
The orphan G-protein coupled receptor 3 (GPR3) belongs to class A G-protein coupled receptors (GPCRs) and is highly expressed in central nervous system neurons. Among other functions, it is likely associated with neuron differentiation and maturation. Recently, GPR3 has also been linked to the production of Aβ peptides in neurons. Unfortunately, the lack of experimental structural information for this receptor hampers a deep characterization of its function. Here, using an in-silico and in-vitro combined approach, we describe, for the first time, structural characteristics of GPR3 receptor underlying its function: the agonist binding site and the allosteric sodium binding cavity. We identified and validated by alanine-scanning mutagenesis the role of three functionally relevant residues: Cys2676.55, Phe1203.36 and Asp2.50. The latter, when mutated into alanine, completely abolished the constitutive and agonist-stimulated adenylate cyclase activity of GPR3 receptor by disrupting its sodium binding cavity. Interestingly, this is correlated with a decrease in Aβ production in a model cell line. Taken together, these results suggest an important role of the allosteric sodium binding site for GPR3 activity and open a possible avenue for the modulation of Aβ production in the Alzheimer's Disease.