Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures

Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta (All) in the brain. A beta oligomers are believed to cause synapse damage resulting in the memory deficits that are characteristic of this disease. Since the loss of synaptic proteins in the brain correlates closely with the degree of dementia in Alzheimer's disease, the process of AD-induced synapse damage was investigated in cultured neurons by measuring the loss of synaptic proteins. Soluble A beta oligomers, derived from Alzheimer's-affected brains, caused the loss of cysteine string protein and synaptophysin from neurons. When applied to synaptosomes A beta oligomers increased cholesterol concentrations and caused aberrant activation of cytoplasmic phospholipase A(2) (cPLA(2)). In contrast, A beta monomer preparations did not affect cholesterol concentrations or activate synaptic cPLA(2), nor did they damage synapses. The A beta oligomer-induced aggregation of cellular prion proteins (PrPc) at synapses triggered the activation of cPLA(2) that leads to synapse degeneration. Critically, A beta monomer preparations did not cause the aggregation of PrPc; rather they reduced the A beta oligomer-induced aggregation of PrPc. The presence of A beta monomer preparations also inhibited the A beta oligomer-induced increase in cholesterol concentrations and activation of cPLA(2) in synaptosomes and protected neurons against the A beta oligomer-induced synapse damage. These results support the hypothesis that A beta monomers are neuroprotective. We hypothesise that synapse damage may result from a pathological A beta monomer:oligomer ratio rather than the total concentrations of A beta within the brain.