Age-related amyloidosis outside the brain: A state-of-the-art review

Tasaki, Masayoshi; Lavatelli, Francesca; Obici, Laura; Obayashi, Konen; Miyamoto, Takeshi; Merlini, Giampaolo; Palladini, Giovanni; Ando, Yukio; Ueda, Mitsuharu

doi:10.1016/j.arr.2021.101388

Cited by 20 publications

(10 citation statements)

References 108 publications

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“…Gene set enrichment comparative analysis of Def-Ts and Rep-Ts suggests the possibility of alternative etiologies for these tumors and supports the notion that oxyphil cells in either context are lineal descendants of chief cells. The differential expression in parathyroid tumors of genes associated with beta-amyloid signaling reveals a potential connection between the increased amyloid burden in aging adults ( 62 , 63 ) and the heightened incidence of PHPT among older individuals ( 64 ). Collectively, these findings suggest that PHPT in vitamin D-deficient patients may be a distinct subset of the disease with an alternative etiology, tumor composition, and cellular behavior.…”

Section: Discussionmentioning

confidence: 99%

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

Chang

Sosa

et al. 2023

PNAS Nexus

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Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder characterized by disrupted calcium homeostasis secondary to inappropriately elevated parathyroid hormone (PTH) secretion. Low levels of serum 25-hydroxyvitamin D (25OHD) are significantly more prevalent in PHPT patients than in the general population (1-3), but the basis for this association remains unclear. We employed a spatially-defined in situ whole-transcriptomics and selective proteomics profiling approach to compare gene expression patterns and cellular composition in parathyroid adenomas from vitamin D-deficient or vitamin D-replete PHPT patients. A cross-sectional panel of eucalcemic cadaveric donor parathyroid glands were examined in parallel as normal tissue controls. Here, we report that parathyroid tumors from vitamin D-deficient PHPT patients (Def-Ts) are intrinsically different from those of vitamin D-replete patients (Rep-Ts) of similar age and pre-operative clinical presentation. Parathyroid oxyphil cell content is markedly higher in Def-Ts (47.8%) relative to Rep-Ts (17.8%) and normal donor glands (7.7%). Vitamin D-deficiency is associated with increased expression of electron transport chain and oxidative phosphorylation pathway components. Parathyroid oxyphil cells, while morphologically distinct, are comparable to chief cells at the transcriptional level, and vitamin D-deficiency affects the transcriptional profiles of both cell types in a similar manner. These data suggest that oxyphil cells are derived from chief cells and imply that their increased abundance may be induced by low vitamin D status. Geneset enrichment analysis reveals that pathways altered in Def-Ts are distinct from Rep-Ts, suggesting alternative tumor etiologies in these groups. Increased oxyphil content may thus be a morphological indicator of tumor-predisposing cellular stress.

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Section: Discussionmentioning

confidence: 99%

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

Chang

Sosa

et al. 2023

PNAS Nexus

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“…Hypoxia stress caused the induction of amyloidosis-autophagy-EMT cell signaling interactions, beginning with amyloidosis ( Cheboub et al, 2019 ; Phua, 2021 ) to allow cells to enter a dormant/resting stage ( Audas et al, 2016 ; Mizejewski, 2017 ; Pavliukeviciene et al, 2019 ). Age-related amyloidoses ( Rubel et al, 2020 ; Tasaki et al, 2021 ) are increasingly being discussed in the mainstream literature, including a range of organs: brain/Alzheimer’s ( Shea et al, 2019 ; Schweighauser et al, 2022 ), renal amyloidosis ( Gupta N. et al, 2020 ; Herrera, 2021 ; Gurung and Li, 2022 ), eyes/Alzheimer’s retinopathy ( Mirzaei et al, 2020 ), type 2 diabetes/Alzheimer’s ( Wang and Westermark, 2021 ), and cardiac amyloidosis ( Garcia-Pavia et al, 2021 ; Hänselmann et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

Phua

2023

Front. Aging

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Aging-related hypoxia, oxidative stress, and inflammation pathophysiology are closely associated with human age-related carcinogenesis and chronic diseases. However, the connection between hypoxia and hormonal cell signaling pathways is unclear, but such human age-related comorbid diseases do coincide with the middle-aging period of declining sex hormonal signaling. This scoping review evaluates the relevant interdisciplinary evidence to assess the systems biology of function, regulation, and homeostasis in order to discern and decipher the etiology of the connection between hypoxia and hormonal signaling in human age-related comorbid diseases. The hypothesis charts the accumulating evidence to support the development of a hypoxic milieu and oxidative stress-inflammation pathophysiology in middle-aged individuals, as well as the induction of amyloidosis, autophagy, and epithelial-to-mesenchymal transition in aging-related degeneration. Taken together, this new approach and strategy can provide the clarity of concepts and patterns to determine the causes of declining vascularity hemodynamics (blood flow) and physiological oxygenation perfusion (oxygen bioavailability) in relation to oxygen homeostasis and vascularity that cause hypoxia (hypovascularity hypoxia). The middle-aging hypovascularity hypoxia hypothesis could provide the mechanistic interface connecting the endocrine, nitric oxide, and oxygen homeostasis signaling that is closely linked to the progressive conditions of degenerative hypertrophy, atrophy, fibrosis, and neoplasm. An in-depth understanding of these intrinsic biological processes of the developing middle-aged hypoxia could provide potential new strategies for time-dependent therapies in maintaining healthspan for healthy lifestyle aging, medical cost savings, and health system sustainability.

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“…Whilst systemic amyloidosis has traditionally been associated with the presence of destabilized protein variants, such as lysozyme or transthyretin (TTR), or markedly increased plasma protein concentrations (SAA) ( Merlini and Bellotti, 2003 ), epidemiological studies have shown that there is also an association of amyloid with aging ( Blumenthal, 2004 ; Trigo et al, 2019 ; Tasaki et al, 2021 ) ( Table 1 ). This is particularly true for amyloid diseases caused by normal circulating levels of wild type proteins such as TTR ( Nativi-Nicolau et al, 2021 ).…”

Section: Amyloidosis Is An Aging Associated Diseasementioning

confidence: 99%

Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms

Faravelli

Mondani

Mangione

et al. 2022

Front. Mol. Biosci.

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The globular to fibrillar transition of proteins represents a key pathogenic event in the development of amyloid diseases. Although systemic amyloidoses share the common characteristic of amyloid deposition in the extracellular matrix, they are clinically heterogeneous as the affected organs may vary. The observation that precursors of amyloid fibrils derived from circulating globular plasma proteins led to huge efforts in trying to elucidate the structural events determining the protein metamorphosis from their globular to fibrillar state. Whereas the process of metamorphosis has inspired poets and writers from Ovid to Kafka, protein metamorphism is a more recent concept. It is an ideal metaphor in biochemistry for studying the protein folding paradigm and investigating determinants of folding dynamics. Although we have learned how to transform both normal and pathogenic globular proteins into fibrillar polymers in vitro, the events occurring in vivo, are far more complex and yet to be explained. A major gap still exists between in vivo and in vitro models of fibrillogenesis as the biological complexity of the disease in living organisms cannot be reproduced at the same extent in the test tube. Reviewing the major scientific attempts to monitor the amyloidogenic metamorphosis of globular proteins in systems of increasing complexity, from cell culture to human tissues, may help to bridge the gap between the experimental models and the actual pathological events in patients.

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Age-related amyloidosis outside the brain: A state-of-the-art review

Cited by 20 publications

References 108 publications

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms

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