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 Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta 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 Abeta, the alphav integrin extracellular cell matrix-binding protein and the cytokine TNFalpha (tumour necrosis factor alpha) type-1 death receptor mediate Abeta oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFalpha or genetic knockout of TNF-R1s (type-1 TNFalpha receptors) prevented Abeta-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to alphav-containing integrins abrogated LTP block by Abeta. Protection against the synaptic plasticity-disruptive effects of soluble Abeta 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 Abeta oligomers in preclinical AD.
AD (Alzheimer's disease) is characterized by a progressive and devastating mental decline that is usually presaged by impairment of a form of memory dependent on medial temporal lobe structures, including the hippocampus. The severity of clinical dementia correlates positively with the cerebral load of the AD-related protein Abeta (amyloid beta), particularly in its soluble form rather than the insoluble fibrillar Abeta found in amyloid plaques. Recent research in animal models of AD has pointed to a potentially important role for rapid disruptive effects of soluble species of Abeta on neural function in causing a relatively selective impairment of memory early in the disease. Our experiments assessing the mechanisms of Abeta inhibition of LTP (long-term potentiation), a correlate of memory-related synaptic plasticity, in the rodent hippocampus showed that low-n oligomers were the soluble Abeta species primarily responsible for the disruption of synaptic plasticity in vivo. Exogenously applied and endogenously generated anti-Abeta antibodies rapidly neutralized and prevented the synaptic plasticity disrupting effects of these very potent Abeta oligomers. This suggests that active or passive immunotherapeutic strategies for early AD should target Abeta oligomers in the brain. The ability of agents that reduce nitrosative/oxidative stress or antagonize stress-activated kinases to prevent Abeta inhibition of LTP in vitro points to a key role of these cellular mechanisms at very early stages in Abeta-induced neuronal dysfunction. A combination of antibody-mediated inactivation of Abeta oligomers and pharmacological prevention of cellular stress mechanisms underlying their synaptic plasticity disrupting effects provides an attractive strategy in the prevention of early AD.
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