Synaptic dysfunction and neuronal loss are associated with the onset of symptomatic Alzheimer’s disease (AD). Although deposition of β-amyloid (Aβ) in the brain is widely accepted as a key pathogenic event in AD, how Aβ contributes to development of cognitive dysfunction is unclear. Aβ is released during neuronal activity and has been found to have beneficial effects on synaptic plasticity and memory formation. The enzyme neprilysin, which clears Aβ, declines with age and is expressed at reduced concentrations in AD patients. Age is the greatest risk factor for AD, suggesting that prolonged Aβ concentration released at synapses during neuronal activity might not be cleared as rapidly and might decrease synaptic plasticity at higher levels. Therefore, understanding the relationship between Aβ dynamics and synaptic dysfunction could lead to new therapeutic targets to prevent or delay AD.
Koppensteiner et al. investigated how the beneficial effects of Aβ on synaptic plasticity and memory change over time. Using primary hippocampal neuronal cultures, the authors applied 200 picomolar Aβ, a concentration that mimics endogenous expression, for both short and prolonged exposures. Short exposures of 20 to 40 min increased synaptic plasticity, and exposures lasting several hours decreased it. Longer exposures to Aβ induced actin polymerization and other cytoskeletal-mediated changes in synaptic protein distribution, such as the synaptic vesicle protein synaptophysin. Last, mouse dorsal hippocampi were infused with Aβ for short and long exposures during fear conditioning. Mice that received short exposures to Aβ showed enhanced memory compared with controls. By contrast, the memories of mice that received longer exposures to Aβ were impaired.
A critical knowledge gap in AD research is the role Aβ plays in the development of cognitive dysfunction. In this paper, Koppensteiner et al. found a time-dependent reversal in the effects of Aβ on synaptic plasticity and memory. They suggest a model in which the decreased synaptic plasticity triggered by prolonged exposure to Aβ ultimately leads to symptomatic AD. However, this study is limited by the absence of data showing that Aβ concentration is persistently elevated to toxic amounts in vivo for one hour or more during normal neuronal activity. Further studies in both humans and animal models are needed to determine if the Aβ concentrations in living organisms under normal physiological conditions exert negative effects on memory and synaptic plasticity.
P. Koppensteiner et al., Time-dependent reversal of synaptic plasticity induced by physiological concentrations of oligomeric Aβ42: An early index of Alzheimer’s disease. Sci. Rep. 10.1038/srep32553 (2016). [Full Text]
- Copyright © 2016, American Association for the Advancement of Science