Amyloid β Protein (25‐35) Phosphorylates MARCKS Through Tyrosine Kinase‐Activated Protein Kinase C Signaling Pathway in Microglia

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Abstract
: Myristoylated alanine‐rich C kinase substrate (MARCKS) is a widely distributed specific protein kinase C (PKC) substrate and has been implicated in membrane trafficking, cell motility, secretion, cell cycle, and transformation. We found that amyloid β protein (Aβ) (25‐35) and Aβ (1‐40) phosphorylate MARCKS in primary cultured rat microglia. Treatment of microglia with Aβ (25‐35) at 10 nM or 12‐O‐tetradecanoylphorbol 13‐acetate (1.6 nM) led to phosphorylation of MARCKS, an event inhibited by PKC inhibitors, staurosporine, calphostin C, and chelerythrine. The Aβ (25‐35)‐induced phosphorylation of MARCKS was inhibited by pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A, but not with pertussis toxin. PKC isoforms α, δ, and £ were identified in microglia by immunocytochemistry and western blots using isoform‐specific antibodies. PKC‐δ was tyrosine‐phosphorylated by the treatment of microglia for 10 min with Aβ (25‐35) at 10 nM. Other PKC isoforms α and £ were tyrosine‐phosphorylated by Aβ (25‐35), but only to a small extent. We propose that a tyrosine kinase‐activated PKC pathway is involved in the Aβ (25‐35)‐induced phosphorylation of MARCKS in rat microglia.