| First Author | Panes-Fernandez J | Year | 2023 |
| Journal | Biomed Pharmacother | Volume | 162 |
| Pages | 114596 | PubMed ID | 36989728 |
| Mgi Jnum | J:346044 | Mgi Id | MGI:7485519 |
| Doi | 10.1016/j.biopha.2023.114596 | Citation | Panes-Fernandez J, et al. (2023) TG2 promotes amyloid beta aggregates: Impact on ER-mitochondria crosstalk, calcium homeostasis and synaptic function in Alzheimer's disease. Biomed Pharmacother 162:114596 |
| abstractText | Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly affects the elderly. AD's main features have been related to cellular and molecular events, including the aberrant aggregation of the amyloid beta peptide (Abeta), Ca(2+) dyshomeostasis, and increased mitochondria-associated membranes (MAMs). Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose primary role is the Ca(2+)-dependent proteins transamidation, including the Abeta peptide. TG2 activity has been closely related to cellular damage and death. We detected increased TG2 levels in neuronal cells treated with Abeta oligomers (AbetaOs) and hippocampal slices from J20 mice using cellular and molecular approaches. In this work, we characterized the capacity of TG2 to interact and promote Abeta toxic aggregates (AbetaTG2). AbetaTG2 induced an acute increase in intracellular Ca(2+), miniature currents, and hiperexcitability, consistent with an increased mitochondrial Ca(2+) overload, IP3R-VDAC tethering, and mitochondria-endoplasmic reticulum contacts (MERCs). AbetaTG2 also decreased neuronal viability and excitatory postsynaptic currents, reinforcing the idea of synaptic failure associated with MAMs dysregulation mediated by TG2. Z-DON treatment, TG2 inhibitor, reduced calcium overload, mitochondrial membrane potential loss, and synaptic failure, indicating an involvement of TG2 in a toxic cycle which increases Abeta aggregation, Ca(2+) overload, and MAMs upregulation. These data provide novel information regarding the role TG2 plays in synaptic function and contribute additional evidence to support the further development of TG2 inhibitors as a disease-modifying strategy for AD. |
