The Structure Biology of Tau and Clue for Aggregation Inhibitor Design

Wang, Dan; Huang, Xianlong; Yan, Lü; Zhou, Luo-Qi; Yan, Chang; Wu, Jinhu; Su, Zhengding; Huang, Yongqi

doi:10.1007/s10930-021-10017-6

Cited by 13 publications

(8 citation statements)

References 183 publications

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“…In this animal model, we observed that lipid domains increased in size paralleling the evolution of neuropathological hallmark of the disease, namely amyloid plaques [24]. This increase in lipid rafts supports the lipid raft hypothesis of AD by contributing with another factor form microdomains to increase the production of βamyloid, as wider regions would enhance the accumulation of amyloidogenic components of APP processing [3,4].…”

Section: Introductionsupporting

confidence: 78%

“…Neuropathological hallmarks of AD include proteinopathies causing amyloid plaques, by aggregation of insoluble amyloid β peptides, and neurofibrillary tangles, by hyperphosphorylation of tau protein, both of which evolve with disease progression. The mechanisms of formation of extracellular β-amyloid accumulations and the formation of intracellular neurofibrillary tangles have received considerable attention and current knowledge supports the widely accepted amyloid cascade hypothesis [3,4]. It is accepted that these neuropathological features can explain the symptoms and the evolution of the pathology in late stages of sporadic LOAD and also in the genetic form which causes FAD, though there exist considerable differences in the development of both forms.…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

Santos

Dı́az

2021

IJMS

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Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.

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Section: Introductionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 97%

Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

Santos

Dı́az

2021

IJMS

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“…Tau protein, produced by the alternative splicing of the MAPT gene, is predominantly present in neuronal and glial axons, where it is vitally important for many physiological processes. It is highly charged and hydrophilic, however, in AD, hyperphosphorylated (P-Tau) tau monomers tend to aggregate first in oligomers and then in neurofibrillary tangles [ 16 ] (for details, see Section 2.2 ).…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s Disease: Significant Benefit from the Yeast-Based Models

Epremyan

Mamaev

Zvyagilskaya

2023

IJMS

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Alzheimer’s disease (AD) is an age-related, multifaceted neurological disorder associated with accumulation of aggregated proteins (amyloid Aβ and hyperphosphorylated tau), loss of synapses and neurons, and alterations in microglia. AD was recognized by the World Health Organization as a global public health priority. The pursuit of a better understanding of AD forced researchers to pay attention to well-defined single-celled yeasts. Yeasts, despite obvious limitations in application to neuroscience, show high preservation of basic biological processes with all eukaryotic organisms and offer great advantages over other disease models due to the simplicity, high growth rates on low-cost substrates, relatively simple genetic manipulations, the large knowledge base and data collections, and availability of an unprecedented amount of genomic and proteomic toolboxes and high-throughput screening techniques, inaccessible to higher organisms. Research reviewed above clearly indicates that yeast models, together with other, more simple eukaryotic models including animal models, C. elegans and Drosophila, significantly contributed to understanding Aβ and tau biology. These models allowed high throughput screening of factors and drugs that interfere with Aβ oligomerization, aggregation and toxicity, and tau hyperphosphorylation. In the future, yeast models will remain relevant, with a focus on creating novel high throughput systems to facilitate the identification of the earliest AD biomarkers among different cellular networks in order to achieve the main goal—to develop new promising therapeutic strategies to treat or prevent the disease.

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“…(1) Although the pathology behind the neurodegeneration found with AD is still not fully understood, there are two main proteins associated with the toxicity cascade, betaamyloid and tau, which comprise the hallmarks of AD. (2)(3)(4)(5)(6)(7) The abnormal processing of the amyloid precursor protein (APP) leading to accumulation of beta amyloid peptide (Aβ) results in plaques or clusters referred to as senile plaques (SPs). (2) Meanwhile, the hyperphosphorylation of the intracellular microtubule-binding protein tau leads to an abundance of neurofibrillary tangles (NFTs).…”

Section: Introductionmentioning

confidence: 99%

“…(2) Meanwhile, the hyperphosphorylation of the intracellular microtubule-binding protein tau leads to an abundance of neurofibrillary tangles (NFTs). (3) Moreover, AD patients present with myriad other symptoms such as cellular signaling dysregulation, impairment of insulin signaling, chronic inflammation, synapse loss, cellular metabolism disorders, and oxidative stress. (4)(5)(6)(7) There are many contributing factors to AD occurrence, with research suggesting that lifestyle, environmental, and genetic factors all play an important role.…”

Section: Introductionmentioning

confidence: 99%

Degradation of Bone Quality in a Transgenic Mouse Model of Alzheimer′s Disease

LLabre

Gil

Amatya

et al. 2020

Journal of Bone and Mineral Research

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Alzheimer′s disease (AD) patients present with symptoms such as impairment of insulin signaling, chronic inflammation, and oxidative stress. Furthermore, there are comorbidities associated with AD progression. For example, osteoporosis is common with AD wherein patients exhibit reduced mineralization and a risk for fragility fractures. However, there is a lack of understanding on the effects of AD on bone beyond loss of bone density. To this end, we investigated the effects of AD on bone quality using the 5XFAD transgenic mouse model in which 12‐month‐old 5XFAD mice showed accumulation of amyloid‐beta (Aβ42) compared with wild‐type (WT) littermates (n = 10/group; 50% female, 50% male). Here, we observed changes in cortical bone but not in cancellous bone quality. Both bone mass and bone quality, measured in femoral samples using imaging (micro‐CT, confocal Raman spectroscopy, X‐ray diffraction [XRD]), mechanical (fracture tests), and chemical analyses (biochemical assays), were altered in the 5XFAD mice compared with WT. Micro‐CT results showed 5XFAD mice had lower volumetric bone mineral density (BMD) and increased endocortical bone loss. XRD results showed decreased mineralization with smaller mineral crystals. Bone matrix compositional properties, from Raman, showed decreased crystallinity along with higher accumulation of glycoxidation products and glycation products, measured biochemically. 5XFAD mice also demonstrated loss of initiation and maximum toughness. We observed that carboxymethyl‐lysine (CML) and mineralization correlated with initiation toughness, whereas crystal size and pentosidine (PEN) correlated with maximum toughness, suggesting bone matrix changes predominated by advanced glycation end products (AGEs) and altered/poor mineral quality explained loss of fracture toughness. Our findings highlight two pathways to skeletal fragility in AD through alteration of bone quality: (i) accumulation of AGEs; and (ii) loss of crystallinity, decreased crystal size, and loss of mineralization. We observed that the accumulation of amyloidosis in brain correlated with an increase in several AGEs, consistent with a mechanistic link between elevated Aβ42 levels in the brain and AGE accumulation in bone. © 2022 American Society for Bone and Mineral Research (ASBMR).

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The Structure Biology of Tau and Clue for Aggregation Inhibitor Design

Cited by 13 publications

References 183 publications

Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

Alzheimer’s Disease: Significant Benefit from the Yeast-Based Models

Degradation of Bone Quality in a Transgenic Mouse Model of Alzheimer′s Disease

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