γ‐Secretase component presenilin is important for microglia β‐amyloid clearance

@article{Farfara2011SecretaseCP,
  title={$\gamma$‐Secretase component presenilin is important for microglia $\beta$‐amyloid clearance},
  author={Dorit Farfara and Dorit Trudler and Niva Segev-Amzaleg and Ronit Galron and Reuven Stein and Dan Frenkel},
  journal={Annals of Neurology},
  year={2011},
  volume={69}
}
The cleavage of amyloid precursor protein by γ‐secretase is an important aspect of the pathogenesis of Alzheimer's disease. γ‐Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the γ‐secretase catalytic site. Our aim was to investigate whether γ‐secretase can be important for microglial phagocytosis of Alzheimer's disease β‐amyloid. 
γ‐Secretase in microglia – implications for neurodegeneration and neuroinflammation
TLDR
The involvement of γ‐secretase in the regulation of microglial functions, and the potential relevance of these processes under physiological and pathophysiological conditions are discussed.
Presenilins and γ-Secretase in Membrane Proteostasis
TLDR
This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy.
Comparative Interactome Investigation of γ-secretase Complex in Alzheimer’s Disease
TLDR
The study revealed mature γsecretase complexes containing PS1 or mutant PS1 to be indistinguishable in their protein composition, confirmed several previously proposed γ-secretase interactors, and identified many others that may fulfill distinct roles.
The very many faces of presenilins and the γ-secretase complex
TLDR
A selective survey of the multitude of functions of presenilins and the γ-secretase complex is presented, suggesting that its evolution and functions might be much more diversified than previously expected.
DJ‐1 deficiency impairs autophagy and reduces alpha‐synuclein phagocytosis by microglia
TLDR
It is discovered that DJ‐1 KD microglia exhibit an impaired autophagy‐dependent degradation of p62 and LC3 proteins, and that manipulation ofautophagy had less effect on α‐Syn uptake and clearance in DJ‐ 1 KDmicroglia, compared to control microglIA.
Activated Cyclin-Dependent Kinase 5 Promotes Microglial Phagocytosis of Fibrillar β-Amyloid by Up-regulating Lipoprotein Lipase Expression*
TLDR
A potential role of the CDK5/p25-LPL signaling pathway in Aβ phagocytosis by microglia is revealed and a new insight is provided into the molecular pathogenesis of Alzheimer disease.
Mechanisms of Aβ Clearance and Degradation by Glial Cells
TLDR
The mechanisms of Aβ degradation by glial cells include the production of proteases, including neprilysin, the insulin degrading enzyme, and the endothelin-converting enzymes, able to hydrolyse Aβ at different cleavage sites.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 58 REFERENCES
γ‐Secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila
  • C. Micchelli, W. Esler, M. Wolfe
  • Biology, Chemistry
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2003
TLDR
The results show that genetics and developmental biology can help elucidate the in vivo site of action of pharmacological agents and suggest that organisms such as Drosophila may be used as simple models for in vivo prescreening of drug candidates.
Gamma-secretase: structure, function, and modulation for Alzheimer's disease.
  • M. Wolfe
  • Biology
    Current topics in medicinal chemistry
  • 2008
Gamma-secretase proteolyzes a variety of membrane-associated fragments derived from type I integral membrane proteins, including the amyloid beta-protein precursor, involved in Alzheimer's disease,
The Transmembrane Aspartates in Presenilin 1 and 2 Are Obligatory for γ-Secretase Activity and Amyloid β-Protein Generation*
TLDR
It is concluded that presenilins, and their TM aspartates in particular, are attractive targets for lowering Aβ therapeutically to prevent Alzheimer's disease.
Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils
TLDR
It is reported that class A scavenger receptors mediate adhesion of rodent microglia and human monocytes to β-amyloid fibril-coated surfaces leading to secretion of reactive oxygen species and cell immobilization.
Gamma secretase–mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke
TLDR
Findings suggest that Notch signaling may be a therapeutic target for treatment of stroke and related neurodegenerative conditions.
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
TLDR
Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
Degradation of Amyloid β-Protein by a Metalloprotease Secreted by Microglia and Other Neural and Non-neural Cells*
TLDR
It is concluded that secreted A β1-40 and Aβ1-42 peptides are constitutively degraded by a metalloprotease released by microglia and other neural cells, providing a potential mechanism for the clearance of Aβ in brain tissue.
Therapeutic Potential of γ -Secretase Inhibitors and Modulators
TLDR
Clinical studies with other potent  -secretase inhibitors will tell us if these pharmacodynamic and tolerability profiles observed in humans are typical of the pharmacological class or are compound-specific.
Therapeutic potential of gamma-secretase inhibitors and modulators.
  • B. Imbimbo
  • Biology
    Current topics in medicinal chemistry
  • 2008
TLDR
It has been suggested that biomarkers for efficacy (cerebrospinal fluid Abeta42 levels) and toxicity (plasma adipsin levels) would be helpful in initial clinical trials with gamma-secretase inhibitors.
Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils.
TLDR
It is reported that class A scavenger receptors mediate adhesion of rodent microglia and human monocytes to beta-amyloid fibril-coated surfaces leading to secretion of reactive oxygen species and cell immobilization in Alzheimer's disease.
...
1
2
3
4
5
...