Related Experiment Video

Updated: May 13, 2026

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
09:12

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates

Published on: January 30, 2014

16.1K

SYK coordinates neuroprotective microglial responses in neurodegenerative disease

Hannah Ennerfelt1, Elizabeth L Frost2, Daniel A Shapiro2

  • 1Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia (UVA), Charlottesville, VA 22908, USA; Neuroscience Graduate Program, UVA, Charlottesville, VA 22908, USA; Cell and Molecular Biology Graduate Training Program, UVA, Charlottesville, VA 22908, USA.

Cell
|October 18, 2022
PubMed

Insights

Spleen tyrosine kinase (SYK) is crucial for microglia function in Alzheimer's disease models. Its deletion worsens amyloid beta deposition and neuropathology, highlighting SYK's role in neuroprotection.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Microglia, the brain's immune cells, play a key role in clearing neurotoxic material like amyloid beta (Aβ) and myelin debris in neurodegenerative diseases.
  • The intracellular signaling pathways that regulate beneficial microglial functions, particularly their phagocytic activity, are not fully understood.

Purpose of the Study:

  • To investigate the role of Spleen Tyrosine Kinase (SYK) in microglial function and its impact on Alzheimer's disease (AD) and demyelinating disease pathology.
  • To elucidate the molecular mechanisms by which SYK signaling influences microglial responses to neurotoxic stimuli.

Main Methods:

  • Utilized the 5xFAD mouse model of Alzheimer's disease to study the effects of targeted SYK deletion in microglia.
  • Analyzed Aβ deposition, neuropathology, cognitive function, and the development of disease-associated microglia (DAM).
  • Investigated SYK's role in microglial phagocytosis and signaling pathways, including AKT/GSK3β, in both AD and demyelinating disease contexts.

Main Results:

  • Targeted deletion of SYK in microglia exacerbated Aβ deposition, neuropathology, and cognitive deficits in the 5xFAD mouse model.
  • Disruption of SYK signaling impaired DAM development, altered AKT/GSK3β signaling, and restricted microglial Aβ phagocytosis.
  • Receptor-mediated activation of SYK was found to limit Aβ load, and SYK was critical for microglial phagocytosis and DAM acquisition in demyelinating disease.

Conclusions:

  • SYK is a critical intracellular signaling molecule that orchestrates neuroprotective functions of microglia.
  • SYK signaling is essential for effective microglial phagocytosis of Aβ and myelin debris, and for the development of disease-associated microglia.
  • These findings expand the understanding of innate immune signaling in beneficial microglial responses to neurotoxic material, offering potential therapeutic targets for neurodegenerative diseases.
Keywords:
Alzheimer’s diseaseSYKamyloid betadisease-associated microgliaexperimental autoimmune encephalomyelitismicrogliamultiple sclerosisneurodegenerative diseaseneuroimmunologyphagocytosis

More Related Videos

Rapid and Refined CD11b Magnetic Isolation of Primary Microglia with Enhanced Purity and Versatility07:54

Rapid and Refined CD11b Magnetic Isolation of Primary Microglia with Enhanced Purity and Versatility

Published on: April 13, 2017

9.9K
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation10:21

Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation

Published on: February 16, 2018

19.4K

Related Concept Videos

Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
Ligand-Gated Ion Channel Receptor: Gating Mechanism01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
Neurochemical Transmission: Sites of Drug Action01:26

Neurochemical Transmission: Sites of Drug Action

Neurochemical transmission, the conduction of electrical impulses between neurons mediated by neurotransmitters, plays a vital role in various physiological processes. Autonomic drugs exert their effects by modulating neurotransmission within the autonomic nervous system. For instance, drugs such as hemicholinium block the precursor uptake necessary for synthesizing acetylcholine, an essential autonomic neurotransmitter. Following synthesis, neurotransmitters are stored in vesicles. Metyrosine...
Drugs Affecting Neurotransmitter Release or Uptake01:21

Drugs Affecting Neurotransmitter Release or Uptake

Certain drugs can affect how neurotransmitters called catecholamines, are released or taken back up in the adrenergic neuron. They can have different effects on the body's sympathetic transmission. Reserpine, a natural compound found in the Rauwolfia shrub, blocks a transporter called vesicular monoamine transporter (VMAT), which leads to a buildup of catecholamines in the cell and reduces sympathetic transmission. Another drug called guanethidine works in multiple ways, including blocking...
Drugs Affecting Neurotransmitter Synthesis01:29

Drugs Affecting Neurotransmitter Synthesis

Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase, which converts...
Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein01:20

Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein

Antiepileptic drugs, such as levetiracetam (Keppra) and brivaracetam (Briviact), have emerged as crucial tools in managing epilepsy. These medications exert their therapeutic effects by targeting the synaptic vesicle protein SV2A, a transmembrane glycoprotein primarily found in the brain.
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...