γ-Secretase component presenilin is important for microglia β-amyloid clearance.

Abstract

OBJECTIVE:

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.

METHODS:

We investigated the role of γ-secretase in microglia activity toward β-amyloid phagocytosis in cell culture using γ-secretase inhibitors and small hairpin RNA and presenilin-deficient mice.

RESULTS:

We found that γ-secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble β-amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble β-amyloid. Dysfunction in the γ-secretase catalytic site led to an impairment in clearing insoluble β-amyloid from brain sections taken from an Alzheimer's disease mouse model when compared to microglia from wild-type mice.

INTERPRETATION:

We suggest for the first time, a dual role for γ-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic β-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic β-amyloid deposits. Further studies of γ-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention.

• Authors: Dorit Farfara, Dorit Trudler, Niva Segev-Amzaleg, Ronit Galron, Reuven Stein, Dan Frenkel
• Journal: Annals of neurology (Ann Neurol) Vol. 69 Issue 1 Pg. 170-80 (Jan 2011) ISSN: 1531-8249 [Electronic] United States
• PMID: 21280087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 American Neurological Association.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Presenilins
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (metabolism, pathology, physiopathology)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism, physiology)
• Amyloid beta-Peptides (biosynthesis, metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Cells, Cultured
• Macrophages, Peritoneal (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (metabolism, physiology)
• Phagocytosis (physiology)
• Plaque, Amyloid (metabolism, pathology)
• Presenilins (metabolism, physiology)
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Transfection (methods)