Aβ leads to Ca²⁺ signaling alterations and transcriptional changes in glial cells.
The pathogenesis of Alzheimer's disease includes accumulation of toxic amyloid beta (Aβ) peptides. A recently developed cell-permeable peptide, termed Tat-Pro, disrupts the complex between synapse-associated protein 97 (SAP97) and the α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), thereby leading to an alteration of the trafficking of the enzyme, which is important for nonamyloidogenic processing of amyloid precursor protein (APP). We report that Tat-Pro treatment, as well as the treatment with exogenous Aβ, deregulates Ca(2+) homeostasis specifically in astrocytes through increased expression of key components of Ca(2+) signaling, metabotropic glutamate receptor-5 and inositol 1,4,5-trisphosphate receptor-1. This is accompanied by potentiation of (S)-3,5-dihydroxyphenylglycine-induced Ca(2+) transients. Calcineurin inhibition reverts all these effects. Furthermore, our data demonstrate that astrocytes express all the components for the amyloidogenic and nonamyloidogenic processing of APP including APP itself, beta-site APP-cleaving enzyme 1 (BACE1), ADAM10, γ-secretase, and SAP97. Indeed, treatment with Tat-Pro for 48 hours significantly increased the amount of Aβ(1-42) in the medium of cultured astrocytes. Taken together, our results suggest that astroglia might be active players in Aβ production and indicate that the calcium hypothesis of Alzheimer's disease may recognize glial cells as important intermediates.
DiSCAFF, Università degli Studi del Piemonte Orientale Amedeo Avogadro, Novara, Italy.
Ambra A
AA
Grolla
Gohar
G
Fakhfouri
Giulia
G
Balzaretti
Elena
E
Marcello
Fabrizio
F
Gardoni
Pier L
PL
Canonico
Monica
M
DiLuca
Armando A
AA
Genazzani
Dmitry
D
Lim
D051722:ADAM Proteins / Q000494:pharmacology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008565:Membrane Proteins / Q000494:pharmacology*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
D016229:Amyloid beta-Peptides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D010446:Peptide Fragments; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human