TG2 promotes amyloid beta aggregates: Impact on ER-mitochondria crosstalk, calcium homeostasis and synaptic function in Alzheimer’s disease

Panes-Fernández, Jessica; Godoy, Pamela A.; Gavilán, J. F.; Ramírez-Molina, Oscar; Burgos, Carlos F.; Marileo, Ana; Flores-Núñez, Oscar; Castro, Patricio; Ramirez-Molina, Oscar; Yévenes, Gonzalo E.; Muñoz-Montesino, Carola; Fuentealba, Jorge

doi:10.1016/j.biopha.2023.114596

Cited by 8 publications

(3 citation statements)

References 52 publications

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“…In in vitro models, TG2 has been shown to generate a broad range of Aβ oligomers, leading to protofibril-like assemblies [123]. The association between TG2 and Aβ forming toxic aggregates induces an acute mitochondrial Ca 2+ overload, increased mitochondria-endoplasmic-reticulum contacts, and synaptic dysregulation in AD [124]. In APP SWE /PS1 ∆E9 and APP23 mouse models of AD, TG2 protein, as well as its crosslinking activity, are colocalized with Aβ plaques and vascular Aβ in the brain [125].…”

Section: Tg2 In Alzheimer's Diseasementioning

confidence: 99%

“…A commonly used irreversible inhibitor, Z-DON (Z006), has been used to demonstrate the modulation of TG2 in neurite outgrowth and neural differentiation when neurons are exposed to organophosphates [204]. Most recently, Z-DON, reduced molecular events, such as mitochondrial membrane potential loss and synaptic failure, caused by Aβ toxic aggregates in a transgenic model of AD [124]. The Khosla group has synthesized a large series of dihydroisoxazole-based irreversible inhibitors.…”

Section: Irreversible Inhibitorsmentioning

confidence: 99%

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Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Liu,

Mouradian

2024

IJMS

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Neurodegenerative diseases encompass a heterogeneous group of disorders that afflict millions of people worldwide. Characteristic protein aggregates are histopathological hallmark features of these disorders, including Amyloid β (Aβ)-containing plaques and tau-containing neurofibrillary tangles in Alzheimer’s disease, α-Synuclein (α-Syn)-containing Lewy bodies and Lewy neurites in Parkinson’s disease and dementia with Lewy bodies, and mutant huntingtin (mHTT) in nuclear inclusions in Huntington’s disease. These various aggregates are found in specific brain regions that are impacted by neurodegeneration and associated with clinical manifestations. Transglutaminase (TG2) (also known as tissue transglutaminase) is the most ubiquitously expressed member of the transglutaminase family with protein crosslinking activity. To date, Aβ, tau, α-Syn, and mHTT have been determined to be substrates of TG2, leading to their aggregation and implicating the involvement of TG2 in several pathophysiological events in neurodegenerative disorders. In this review, we summarize the biochemistry and physiologic functions of TG2 and describe recent advances in the pathogenetic role of TG2 in these diseases. We also review TG2 inhibitors tested in clinical trials and discuss recent TG2-targeting approaches, which offer new perspectives for the design of future highly potent and selective drugs with improved brain delivery as a disease-modifying treatment for neurodegenerative disorders.

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Section: Tg2 In Alzheimer's Diseasementioning

confidence: 99%

Section: Irreversible Inhibitorsmentioning

confidence: 99%

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Liu,

Mouradian

2024

IJMS

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“…Reduced Drp1 in Tg2576 mice decreases soluble Aβ production in AD progression by reducing mitochondrial dysfunction, maintaining mitochondrial dynamics, and enhancing mitochondrial biogenesis and synaptic activity [117]. In J20 mice, Transglutaminase type 2 can interact with Aβ to form toxic aggregation then induce an acute increase in intracellular Ca 2+ , and an increased mitochondrial Ca 2+ overload, thus affecting ER-mitochondria cross talk [118,119]. Increased basal and coupled respiration in the hippocampus along with a decreased Complex II-dependent respiratory activity were observed in TgCRND8 female mice [120].…”

Section: Mitochondria Dysfunction In Alzheimer's Diseasementioning

confidence: 99%

Effects of Redox Homeostasis and Mitochondrial Damage on Alzheimer’s Disease

Wu,

Hsieh

2023

Antioxidants

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Bioenergetic mitochondrial dysfunction is a common feature of several diseases, including Alzheimer’s disease (AD), where redox imbalance also plays an important role in terms of disease development. AD is an age-related disease and begins many years before the appearance of neurodegenerative symptoms. Intracellular tau aggregation, extracellular β-amyloid (Aβ) deposition in the brain, and even the APOE4 genotype contribute to the process of AD by impairing redox homeostasis and mitochondrial dysfunction. This review summarizes the evidence for the redox imbalance and mitochondrial dysfunction in AD and demonstrates the current therapeutic strategies related to mitochondrial maintenance.

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MAMs and Mitochondrial Quality Control: Overview and Their Role in Alzheimer’s Disease

Luo,

Zhai,

Ding

et al. 2024

Neurochem Res

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TG2 promotes amyloid beta aggregates: Impact on ER-mitochondria crosstalk, calcium homeostasis and synaptic function in Alzheimer’s disease

Cited by 8 publications

References 52 publications

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Pathogenetic Contributions and Therapeutic Implications of Transglutaminase 2 in Neurodegenerative Diseases

Effects of Redox Homeostasis and Mitochondrial Damage on Alzheimer’s Disease

MAMs and Mitochondrial Quality Control: Overview and Their Role in Alzheimer’s Disease

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