Related Experiment Video

Updated: Aug 8, 2026

Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
09:33

Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease

Published on: December 26, 2016

Microglial signaling by amyloid beta protein through mitogen-activated protein kinase mediating phosphorylation of

H Hasegawa1, M Nakai, S Tanimukai

  • 1Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan.

Neuroreport
|August 10, 2001
PubMed

Insights

Amyloid beta activates microglia in Alzheimer disease by phosphorylating MARCKS protein via both PKC and MAPK pathways. This study identifies the mitogen-activated protein kinase pathway as a key player in MARCKS activation.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Myristoylated alanine-rich C kinase substrate (MARCKS) is crucial for cell motility and phagocytosis.
  • MARCKS activation is implicated in Alzheimer disease (AD) pathogenesis, particularly in microglia surrounding amyloid plaques.
  • Previous work identified amyloid beta (Aβ) activating MARCKS via tyrosine kinase and PKC-delta.

Purpose of the Study:

  • To investigate the role of mitogen-activated protein kinase (MAPK) signaling in Aβ-induced MARCKS phosphorylation in microglia.
  • To analyze the cross-talk between protein kinase C (PKC) and MAPK pathways in response to Aβ.
  • To elucidate the specific kinases involved in Aβ-mediated MARCKS activation in rat microglia.

Main Methods:

  • Primary cultured rat microglia were treated with amyloid beta (Aβ).
  • The effect of MAPK kinase inhibitor PD098059 on Aβ-induced MARCKS phosphorylation was assessed.
  • In vitro phosphorylation assays using recombinant MARCKS and extracellularly regulated kinases (ERK) were performed.
  • Sensitivity of MAPK and PKC pathways to wortmannin and specific inhibitors was analyzed.

Main Results:

  • A selective MAPK kinase inhibitor (PD098059) significantly reduced Aβ-induced MARCKS phosphorylation.
  • Aβ induced extracellularly regulated kinases (ERK) activity, which directly phosphorylated MARCKS in vitro.
  • The MAPK pathway was sensitive to wortmannin, while Aβ-induced PKC activation was not.
  • PKC and MAPK pathways showed differential sensitivity to inhibitors, suggesting distinct signaling.

Conclusions:

  • The mitogen-activated protein kinase (MAPK) pathway, potentially involving phosphoinositol 3-kinase, plays a significant role in Aβ-induced MARCKS phosphorylation in microglia.
  • This MAPK-mediated phosphorylation of MARCKS may contribute to microglial activation mechanisms in Alzheimer disease.
  • Distinct signaling pathways are involved in Aβ-induced activation of PKC and MAPK.

More Related Videos

Visualization of Amyloid β Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry09:31

Visualization of Amyloid β Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry

Published on: March 7, 2019

Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils15:04

Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils

Published on: September 28, 2019

Related Concept Videos

Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining, normally used to...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...