Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release.
A common feature of many neurodegenerative disorders is an abundance of activated glial cells (astrocytes and microglia). In Alzheimer's disease (AD), activated astrocytes are in close apposition to and surrounding the amyloid plaques. The mechanisms by which the astrocytes become activated in AD and the consequences of reactive astrocytosis to disease progression are not known. We examined the possibility that the amyloid-beta (Abeta) peptide, a major constituent of the amyloid plaque, could act as a stimulus leading to activation. We found that treatment of rat cortical astrocyte cultures with aggregated Abeta 1-42 peptide induces activation, as assessed by reactive morphological changes and upregulation of selective glial mRNA and proteins, such as the inflammatory cytokine interleukin-1beta. Abeta also stimulates inducible nitric oxide synthase (iNOS) mRNA levels and nitric oxide (NO) release. Abeta 1-42, a major form of amyloid associated with neurotoxicity, activated astrocytes in a time- and dose-dependent manner, whereas a scrambled Abeta 1-42 sequence or Abeta 17-42 had little or no effect. We also determined that the Abeta activity can be found in a supernatant fraction containing soluble Abeta oligomers. Our data suggest that Abeta plays a role in the reactive astrocytosis of AD and that the inflammatory response induced upon glial activation is a critical component of the neurodegenerative process.
Hu
J
J
Dept. of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611-3008, USA.
Akama
K T
KT
Krafft
G A
GA
Chromy
B A
BA
Van Eldik
L J
LJ
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D004790:Enzyme Induction; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007375:Interleukin-1; D010446:Peptide Fragments; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat