Paradigm shift redefining molecular, metabolic and structural events in Alzheimer’s disease involves a proposed contribution by transition metals. Defined lengthy preclinical stage provides new hope to circumvent advancement of disease- and age-related neurodegeneration

Cavaleri, Franco

doi:10.1016/j.mehy.2015.01.044

Cited by 11 publications

(4 citation statements)

References 113 publications

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“…The most accredited one proposes the gain-of-function of β-amyloid ( Bush et al, 2003 ; Bush and Tanzi, 2008 ) after binding Cu 2+ ( Multhaup et al, 1996 ). Alternative and more recent hypotheses ( Lee et al, 2005 ; Cavaleri, 2015 ; Kepp, 2016 ) propose a protective role of β-amyloid against an excess of toxic metals within the brain, designating β-amyloid loss-of-function as a pathogenic process in the disease ( Hua et al, 2011 ; Kepp, 2016 ). APP is thought to possess a normal function in metal export from neurons, and a putative loss of the soluble, functional β-amyloid monomer could cause copper build-up in the cell ( Kepp, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

Bagheri

Squitti

Haertlé

et al. 2018

Front. Aging Neurosci.

175

121

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Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by amyloid plaques in patients’ brain tissue. The plaques are mainly made of β-amyloid peptides and trace elements including Zn2+, Cu2+, and Fe2+. Some studies have shown that AD can be considered a type of metal dyshomeostasis. Among metal ions involved in plaques, numerous studies have focused on copper ions, which seem to be one of the main cationic elements in plaque formation. The involvement of copper in AD is controversial, as some studies show a copper deficiency in AD, and consequently a need to enhance copper levels, while other data point to copper overload and therefore a need to reduce copper levels. In this paper, the role of copper ions in AD and some contradictory reports are reviewed and discussed.

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Section: Introductionmentioning

confidence: 99%

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

Bagheri

Squitti

Haertlé

et al. 2018

Front. Aging Neurosci.

175

121

View full text Add to dashboard Cite

show abstract

“…Recently, Cavaleri proposed a paradigm shift in AD 9 , redefining the pathomechanism in which it is included the contribution of transition metals. The literature indicates that uncontrolled oxidation and downstream inflammation play critical roles in the early stages of the disease by setting in motion its development, and shows that heavy metals can play a significant role in amyloid deposition 10 11 .…”

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confidence: 99%

“…Beta-amyloid might serve as a chelating protein designed to protect the neuron from toxic metals that can exacerbate oxidative load via the Fenton reaction. In later stages, the uncontrolled metals and reactive oxygen species (ROS) overcame the countermeasure of BACE1/β-amyloid protein, leading to Tau hyperphosphorylation with sudden cytoskeletal dysfunction and irreversible neuron loss 9 . Gonzalez-Dominguez et al .…”

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confidence: 99%

Distinctive Pattern of Serum Elements During the Progression of Alzheimer’s Disease

Paglia

Miedico

Cristofano

et al. 2016

Sci Rep

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Element profiling is an interesting approach for understanding neurodegenerative processes, considering that compelling evidences show that element toxicity might play a crucial role in the onset and progression of Alzheimer’s disease (AD). Aim of this study was to profile 22 serum elements in subjects with or at risk of AD. Thirtyfour patients with probable AD, 20 with mild cognitive impairment (MCI), 24 with subjective memory complaint (SMC) and 40 healthy subjects (HS) were included in the study. Manganese, iron, copper, zinc, selenium, thallium, antimony, mercury, vanadium and molybdenum changed significantly among the 4 groups. Several essential elements, such as manganese, selenium, zinc and iron tended to increase in SMC and then progressively to decrease in MCI and AD. Toxic elements show a variable behavior, since some elements tended to increase, while others tended to decrease in AD. A multivariate model, built using a panel of six essential elements (manganese, iron, copper, zinc, selenium and calcium) and their ratios, discriminated AD patients from HS with over 90% accuracy. These findings suggest that essential and toxic elements contribute to generate a distinctive signature during the progression of AD, and their monitoring in elderly might help to detect preclinical stages of AD.

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“… 11 Maestro 21 and PROPKA 22 were used for the H-bond assignments and to determine the most likely protonation states of the titratable residues at pH 7.4. Regarding the parameters employed to describe the hydroxymethyl inhibitor, they were obtained by following the nonstandard residue parameterization procedure implemented in Amber using the Antechamber 23 program from the AmberTools18 24 package. The restrained electrostatic potential method 25 using the HF/6-31G* level was used to define the atomic charges of the inhibitor, while the standard residues were described using the ff14SB forcefield.…”

Section: Methodsmentioning

confidence: 99%

Testing Affordable Strategies for the Computational Study of Reactivity in Cysteine Proteases: The Case of SARS-CoV-2 3CL Protease Inhibition

Ramos-Guzmán

Velázquez‐Libera

Ruiz‐Pernía

et al. 2022

J. Chem. Theory Comput.

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Cysteine proteases are an important target for the development of inhibitors that could be used as drugs to regulate the activity of these kinds of enzymes involved in many diseases, including COVID-19. For this reason, it is important to have methodological tools that allow a detailed study of their activity and inhibition, combining computational efficiency and accuracy. We here explore the performance of different quantum mechanics/molecular mechanics methods to explore the inhibition reaction mechanism of the SARS-CoV-2 3CL protease with a hydroxymethyl ketone derivative. We selected two density functional theory (DFT) functionals (B3LYP and M06-2X), two semiempirical Hamiltonians (AM1d and PM6), and two tight-binding DFT methods (DFTB3 and GFN2-xTB) to explore the free energy landscape associated with this reaction. We show that it is possible to obtain an accurate description combining molecular dynamics simulations performed using tight-binding DFT methods and single-point energy corrections at a higher QM description. The use of a computational strategy that provides reliable results at a reasonable computational cost could assist the in silico screening of possible candidates during the design of new drugs directed against cysteine proteases.

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Paradigm shift redefining molecular, metabolic and structural events in Alzheimer’s disease involves a proposed contribution by transition metals. Defined lengthy preclinical stage provides new hope to circumvent advancement of disease- and age-related neurodegeneration

Cited by 11 publications

References 113 publications

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

Distinctive Pattern of Serum Elements During the Progression of Alzheimer’s Disease

Testing Affordable Strategies for the Computational Study of Reactivity in Cysteine Proteases: The Case of SARS-CoV-2 3CL Protease Inhibition

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