Abstract
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&sub2; (cPLA&sub2;), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E&sub2;. In synaptosomes PGE&sub2; increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA&sub2; demonstrating an inhibitory feedback system. Thus, Aβ/αSN-induced activated cPLA&sub2; produces PGE&sub2; which increases cAMP which in turn suppresses cPLA&sub2; 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&sub2; and protected neurons against synapse damage. These results suggest that drugs that inhibit Aβ-induced activation of cPLA&sub2; and cross the blood-brain barrier may reduce synapse damage in AD.