cAMP-Inhibits Cytoplasmic Phospholipase A(2) and Protects Neurons against Amyloid-β-Induced Synapse Damage

A key event in Alzheimer’s disease (AD) is the production of amyloid-β (Aβ) peptides and the loss of synapses. In cultured neurons Aβ triggered synapse damage as measured by the loss of synaptic proteins. α-synuclein (αSN), aggregates of which accumulate in Parkinson’s disease, also caused synapse damage. Synapse damage was associated with activation of cytoplasmic phospholipase A(2) (cPLA(2)), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E(2). In synaptosomes PGE(2) increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA(2) demonstrating an inhibitory feedback system. Thus, Aβ/αSN-induced activated cPLA(2) produces PGE(2) which increases cAMP which in turn suppresses cPLA(2) and, hence, its own production. Neurons pre-treated with pentoxifylline and caffeine (broad spectrum phosphodiesterase (PDE) inhibitors) or the PDE4 specific inhibitor rolipram significantly increased the Aβ/αSN-induced increase in cAMP and consequently protected neurons against synapse damage. The addition of cAMP analogues also inhibited cPLA(2) and protected neurons against synapse damage. These results suggest that drugs that inhibit Aβ-induced activation of cPLA(2) and cross the blood–brain barrier may reduce synapse damage in AD.