Perlecan domain V inhibits α2 integrin-mediated amyloid-β neurotoxicity.
Amyloid-β (Aβ) peptide is a key component of amyloid plaques, one of the pathological features of Alzheimer's disease. Another feature is pronounced cell loss in the brain leading to an enlargement of the ventricular area and a decrease in brain weight and volume. Aβ plaque deposition and neuronal toxicity can be modeled by treating human cortical neuronal cultures with Aβ and showing robust Aβ deposition and neurotoxicity that is mediated by α2β1 and αvβ1 integrins. The current study expands on these findings by showing that the domain V of perlecan, a known α2 integrin ligand, inhibits Aβ neurotoxicity in an α2 integrin-dependent manner. Additionally, Aβ binds more efficiently to cells expressing activated α2 integrin. Finally the inhibition of Aβ neurotoxicity with domain V is synergistic with inhibitors of αv integrin and β1 integrin. We propose that domain V and potentially other α2 integrin ligands could be a new therapeutic approach for inhibiting the Aβ plaque deposition and neurotoxicity observed in Alzheimer's disease.
Elan Pharmaceuticals Inc., South San Francisco, CA, USA.
Sarah
S
Wright
Christi
C
Parham
Boyeon
B
Lee
Douglas
D
Clarke
Lisa
L
Auckland
Jennifer
J
Johnston
Andrea L
AL
Lawrence
S Kent
SK
Dickeson
Samuel A
SA
Santoro
Irene
I
Griswold-Prenner
Gregory
G
Bix
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology
D016229:Amyloid beta-Peptides; D019812:Heparan Sulfate Proteoglycans; D039421:Integrin alpha2; D008024:Ligands; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C071927:perlecan