Amyloid-beta signalling in oligodendrocytes


KEYWORDS

  • Alzheimer's disease

  • Oligodendrocytes

  • Cell Biology


TECHNIQUES

  • Immunohistochemistry

  • Gene expression

  • Live imaging

Amyloid-beta regulates local protein translation in oligodendrocytes

Myelin degeneration and white matter loss resulting from oligodendrocyte death are early events in Alzheimer's disease (AD) that lead to cognitive deficits. However, the underlying molecular mechanisms remain unknown. One of the hallmarks of AD is the presence of extracellular aggregates of amyloid beta peptide (Aβ), and Aβ oligomers (Aβo) have been proposed to induce changes in oligodendrocytes and myelin. Myelin Associated Oligodendrocyte Basic Protein (MOBP) and Myelin basic protein (MBP) are some of the most abundant proteins in the CNS and both, are locally translated and upregulated by Aβo. We use a combination of in vitro cultures, transgenic mice and human post-mortem samples to study how Aβ or Alzheimer's-associated pathology contributes to myelin dysruption.

Funded by Ministerio de Ciencia e Innovación

Local translation (red) in oligodendrocytes (Phalloidin, green). Nucleus is stained in blue (DAPI)

Amyloid-beta regulation of oligodendrocyte differentiation

Oligodendrocyte (OL) differentiation and myelination processes are tightly controlled by several transcription factors, among which the Myelin Regulatory Factor (MYRF) is of the utmost importance. MYRF is an ER associated protein that needs to undergo a self-cleavage to release its N-terminal fragment from the ER and enter the nucleus, where it works as a transcriptional factor inducing the expression of essential myelin genes such as MBP. Then, GSK3 phosphorylates N-MYRF, and it is degraded by ubiquitin-proteasome system. Although MYRF is not only important but also crucial for OL maturation and CNS myelination, little is known about the effect that Aβ has in this transcriptional factor or the role it may play in AD.

Publications related to this topic

  • Ortiz-Sanz C, Balantzategi U, Quintela-López T, Ruiz A, Luchena C, Zuazo-Ibarra J, Capetillo-Zarate E, Matute C, Zugaza JL, Alberdi E. Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease. Cell Death Dis 2022; 13: 253. [LINK]

  • Ortiz-Sanz C, Gaminde-Blasco A, Valero J, Bakota L, Brandt R, Zugaza JL, Matute C, Alberdi E. Early Effects of Aβ Oligomers on Dendritic Spine Dynamics and Arborization in Hippocampal Neurons. Front Synaptic Neurosci 2020; 12: 2. [LINK]

  • Quintela-López T, Ortiz-Sanz C, Serrano-Regal MP, Gaminde-Blasco A, Valero J, Baleriola J, Sánchez-Gómez MV, Matute C, Alberdi E. Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling. Cell Death Dis 2019; 10: 445. [LINK]

  • Wyssenbach A, Quintela T, Llavero F, Zugaza JL, Matute C, Alberdi E. Amyloid β-induced astrogliosis is mediated by β1-integrin via NADPH oxidase 2 in Alzheimer’s disease. Aging Cell 2016; 15: 1140–1152. [LINK]

  • Alberdi E, Sánchez-Gómez MV, Cavaliere F, Pérez-Samartín A, Zugaza JL, Trullas R, Domercq M, Matute C. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 2010; 47: 264–272. [LINK]