Inhibition of long-term potentiation development in rat hippocampal slice by alpha 2-macroglobulin, an acute-phase...

Alpha-2-macroglobulin (alpha 2M) in the rat and human brain is an acute-phase protein synthesized primarily by astrocytes, and it has been implicated in Alzheimer's disease and other neuropathological processes. The activated forms of alpha 2M, but not the native form, can suppress the neurite outgrowth of the central neurons, presumably through binding to neurotrophic factors and through direct inhibition of neurotrophic factor receptor signal transduction. Since neurotrophic factors are known to be involved in synaptic plasticity, we tested the effect of both the native and methylamine-activated (MA-alpha 2M) forms of alpha 2M on long-term potentiation (LTP) in area CA1 of adult rat hippocampal slice. Neither native alpha 2M nor MA-alpha 2M had an effect on baseline synaptic transmission. LTP induced by 200-Hz trains in the presence of 1.4 microM or 0.14 microM native alpha 2M was indistinguishable from control LTP. Although the presence of MA-alpha 2M at the same concentrations did not interfere with LTP induction, the development and maintenance of potentiation was blocked in a concentration-dependent time course. Results of this study indicate that the accumulation and activation of alpha 2M with inflammatory neuropathologies such as Alzheimer's disease can inhibit synaptic plasticity, which might partly account for the memory deficits seen in these patients.