The essential elements of Alzheimer’s disease

Lei, Peng; Ayton, Scott; Bush, Ashley I.

doi:10.1074/jbc.rev120.008207

Cited by 207 publications

(155 citation statements)

References 430 publications

(499 reference statements)

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“…High metal concentrations have long been suspected to contribute to disease by facilitating improper binding to proteins. Aggregates of proteins such as Alzheimer Aβ peptide, α-synuclein, and amylin have been found with nonnative metal ions bound to them including zinc and copper ( 35 , 36 ). Even a small molar excess of free zinc drives misfolding of p53 ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2)

Wilkens

et al. 2021

Journal of Biological Chemistry

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Aggregation of the circulating protein leukocyte-cell-derived chemotaxin 2 (LECT2) causes amyloidosis of LECT2 (ALECT2), one of the most prevalent forms of systemic amyloidosis affecting the kidney and liver. The I40V mutation is thought to be necessary but not sufficient for ALECT2, with a second, as-yet undetermined condition being required for the disease. EM, X-ray diffraction, NMR, and fluorescence experiments demonstrate that LECT2 forms amyloid fibrils in vitro in the absence of other proteins. Removal of LECT2’s single bound Zn 2+ appears to be obligatory for fibril formation. Zinc-binding affinity is strongly dependent on pH: 9–13 % of LECT2 is calculated to exist in the zinc-free state over the normal pH range of blood, with this fraction rising to 80 % at pH 6.5. The I40V mutation does not alter zinc-binding affinity or kinetics but destabilizes the zinc-free conformation. These results suggest a mechanism in which loss of zinc together with the I40V mutation leads to ALECT2.

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Section: Discussionmentioning

confidence: 99%

Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2)

Wilkens

et al. 2021

Journal of Biological Chemistry

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“…Bellinger et al (2008) further confirmed that the spatial distributions of SELENOP, Aβ, and NFTs are colocalized in the brains of AD patients, suggesting that SELENOP is associated with AD. Ions of numerous metals, such as aluminum, zinc, copper, and iron, can promote Aβ aggregation during the pathological process of AD (Faller et al, 2014;Lei et al, 2020). Many Sec and Cys residues and a Hisrich domain in SELENOP determine its metal-binding capacity (Turanov et al, 2015).…”

Section: Selenop and Selenowmentioning

confidence: 99%

Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer’s Disease

Zhang

Song

2021

Front. Neurosci.

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Selenium (Se) and its compounds have been reported to have great potential in the prevention and treatment of Alzheimer’s disease (AD). However, little is known about the functional mechanism of Se in these processes, limiting its further clinical application. Se exerts its biological functions mainly through selenoproteins, which play vital roles in maintaining optimal brain function. Therefore, selenoproteins, especially brain function-associated selenoproteins, may be involved in the pathogenesis of AD. Here, we analyze the expression and distribution of 25 selenoproteins in the brain and summarize the relationships between selenoproteins and brain function by reviewing recent literature and information contained in relevant databases to identify selenoproteins (GPX4, SELENOP, SELENOK, SELENOT, GPX1, SELENOM, SELENOS, and SELENOW) that are highly expressed specifically in AD-related brain regions and closely associated with brain function. Finally, the potential functions of these selenoproteins in AD are discussed, for example, the function of GPX4 in ferroptosis and the effects of the endoplasmic reticulum (ER)-resident protein SELENOK on Ca2+ homeostasis and receptor-mediated synaptic functions. This review discusses selenoproteins that are closely associated with brain function and the relevant pathways of their involvement in AD pathology to provide new directions for research on the mechanism of Se in AD.

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“…Recently different strategies have been explored to select an effective disease-modifying agent able to tackle earlier the disease (26). Such studies aimed at targeting different pathological paths involving amyloid plaques and tau aggregations (5), and therapies tackling zinc dyshomeostasis. Classical biomarkers, even the highly sensitive blood-based recently characterised through MS (7,9), are based on cerebral amyloidosis detection or prediction of amyloid positivity leading to a late diagnosis and hence a late therapeutic pharmacological interventions.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…The impact on affected individuals represents an economical burden at the healthcare and caregiver's level (2,3). Up to this day, no effective therapies exist to stop the disease, and the existing ones attempt to slow onset and worsening of symptoms (4,5). This is also because AD diagnosis is carried out too late, when symptoms appear.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Simple Blood-Based Test to Predict Early Onset of Alzheimer’s Using Standard Clinical Mass Spectrometry Platforms

Piccirella¹,

Cristoni²,

Fowler³

et al. 2021

Preprint

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Despite the increasing number of individuals affected by Alzheimer’s disease (AD) every year, no effective therapy has been developed to treat this neurodegenerative disease yet. The current methods for AD diagnosis are effective for clinical confirmation of the disease only when symptoms become apparent, years after molecular damage started within the patients’ brains. As higher expression of a conformationally altered p53 has been correlated with AD, we developed a mass spectrometry-based method for highly sensitive, specific, and reproducible quantification of a p53 conformational variant in plasma samples of patients with known clinical outcome. In particular, we tested the prognostic performance of an AD-specific 2D3A8-immunoselected p53 peptide (AZ 284™) in different sets of individuals progressing from both cognitively unimpaired (CU) and mild cognitive impairment (MCI) patients progressing to AD dementia. Our data showed that quantitative analysis of AZ 284™ is a reliable tool for predicting AD progression up to 6 years prior to dementia onset with AUC >90%. Taken together, these results support the implementation of p53 conformational variant quantification as an affordable and powerful diagnostic tool for early, non-invasive AD diagnosis.

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The essential elements of Alzheimer’s disease

Cited by 207 publications

References 430 publications

Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2)

Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2)

Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer’s Disease

Discovery of Simple Blood-Based Test to Predict Early Onset of Alzheimer’s Using Standard Clinical Mass Spectrometry Platforms

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