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 A2 (cPLA2), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E2. In synaptosomes PGE2 increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA2 demonstrating an inhibitory feedback system. Thus, Aβ/αSN-induced activated cPLA2 produces PGE2 which increases cAMP which in turn suppresses cPLA2 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 cPLA2 and protected neurons against synapse damage. These results suggest that drugs that inhibit Aβ-induced activation of cPLA2 and cross the blood–brain barrier may reduce synapse damage in AD.
Highlights
The amyloid hypothesis maintains that the key event in the pathogenesis of Alzheimer’s disease (AD) is the proteolytic cleavage of the amyloid precursor protein to form neurotoxic amyloid-β (Aβ) peptides [1]
Immunoblots of neuronal extracts showed that the addition of brain extract causes the loss of synapsin-1 and vesicle-associated membrane protein (VAMP)-1 (Figure 1A)
Since cyclic adenosine monophosphate (cAMP) inhibited the activation of cytoplasmic phospholipase A2 (cPLA2) and reduced synapse degeneration, the molecular mechanisms leading to cAMP generation within synaptosomes were examined in detail
Summary
The amyloid hypothesis maintains that the key event in the pathogenesis of Alzheimer’s disease (AD) is the proteolytic cleavage of the amyloid precursor protein to form neurotoxic amyloid-β (Aβ) peptides [1]. Synapse damage is a feature of other neurodegenerative diseases including Parkinson’s disease (PD) and dementia with Lewy bodies [10]. The pathology of these diseases is associated with the formation of oligomeric α-synuclein (αSN) [11,12] and preparations of αSN oligomers trigger synapse damage in cultured neurons [13]. We show that phosphodiesterase (PDE) inhibitors protect cultured neurons against Aβ and αSN-induced synapse damage. PDE inhibitors enhanced the Aβ/αSN-induced increase of cAMP in synapses. High concentrations of cAMP suppressed the Aβ/αSN-induced activation of cytoplasmic phospholipase A2 (cPLA2), a key enzyme in synapse function and structure [14]. The cAMP inhibited the activation of cPLA2 and its own production
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