Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric A beta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble A beta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for A beta, the alpha v integrin extracellular cell matrix-binding protein and the cytokine TNF alpha (tumour necrosis factor alpha) type-1 death receptor mediate A beta oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNF alpha or genetic knockout of TNF-R1s (type-1 TNF alpha receptors) prevented A beta-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to alpha v-containing integrins abrogated LTP block by A beta. Protection against the synaptic plasticity-disruptive effects of soluble A beta was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of A beta oligomers in preclinical AD.