New signaling pathway culpable in Beta-amyloid neurotoxicity

Research Areas:

Neurobiology, Alzheimer's Disease, apoptosis, G proteins, beta-amyloid

Imaging Needs:

Quantifying apoptosis in fixed, organotypic cultures

Imaging System:
  • Zeiss Cell Observer Z1 inverted microscope
  • Zeiss Plan NeoFluar × 2.5 objective
  • Rhodamine filter
  • Hamamatsu ImagEM C9100-13 CCD camera
    • 32 frames/second
    • 512 × 512 pixels resolution
  • ImageJ software
Understanding the brain

New imaging techniques are promising to reveal more about neural connectivities in the brain than ever before. See how Misha Ahrens, Philipp Keller and colleagues use lightsheet microscopy to visualize intact, living zebrafish brain in real time. Read now.

THE QUESTION

How does beta-amyloid lead to neuronal death in Alzheimer’s Disease?

1–42 β-Amyloid (beta-amyloid) peptide has long been considered a major culprit in the pathophysiology of Alzheimer’s Disease. It is associated with cytoskeletal changes in neurons leading to a loss of neurites. The peptide is also a major component of the plaques that mark diseased brain tissue in Alzheimer’s cases. Beta-amyloid is toxic to many cell types in culture, including neurons, but the mechanism by which it leads to cell death remains unknown.

THE BARRIERS

G proteins are important components of signaling networks controlling cellular activity in most cell types. Rac1 is a member of the Rho family of G proteins, known to help control changes in the neuronal cytoskeleton in response to extracellular signals—for example, in synaptogenesis. Could Rac1 play a role in beta-amyloid damage?

THE SOLUTION

1–42 β-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death
L Manterola, M Hernando-Rodríguez, A Ruiz, A Apraiz, O Arrizabalaga, L Vellón, E Alberdi, F Cavaliere, H M Lacerda, S Jimenez, L A Parada, C Matute, and J L Zugaza
Transl Psychiatry. 2013 Jan; 3(1): e219. PMCID: PMC3566727.

Manterola, et al,1 show that beta-amyloid activates a cellular signaling cascade involving the Rac1 G protein axis. They found that Rac1 activity is regulated upstream by phosphatidylinositol 3-kinase (PI3K), phosphoinositoldependent kinase (PDK) and a novel protein kinase C (nPKC). They verified the role of Rac1 activation in beta-amyloid-mediated apoptosis using propidium iodide to identify and quantify apoptotic cells in neuronal organotypic cultures. Images were captured using Hamamatsu’s ImagEM EM-CCD camera. The authors propose the Rac1 pathway as a potential mediator of beta-amyloid toxicity, and a possible target for therapeutic intervention.

THE POSSIBILITIES

Manterola, et al,1 identified neurons that had undergone apoptosis using the Hamamatsu ImagEM EM-CCD camera. Learn how lightsheet microscopy technology, supported by Hamamatsu’s ORCA-Flash4.0 camera and pioneered by Misha Ahrens, Philipp Keller, and colleagues, is poised to shed even more light into how the brain works—read Seeing the Living Brain.

References

  1. Manterola, et al. 1–42 β-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Transl Psychiatry. 2013 Jan; 3(1): e219. PMCID: PMC3566727.
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