Short Term Damage Done by Amyloid in the Brain Appears to be Reversible
This compact study suggests that the damage caused to neurons by the presence of β-amyloid in the short term can largely repair itself if the amyloid is removed. This is one of a number of lines of evidence to indicate that targeted clearance of amyloid should produce reversal of symptoms in Alzheimer's disease in at least the earlier stages, before there is widespread cell death, rather than just a halt to the progression of the condition.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized clinically by memory loss and cognitive decline. Its major pathological hallmarks are extracellular senile plaques and intracellular neurofibrillary tangles, which are composed of amyloid β-protein (Aβ) and phosphorylated tau (p-tau) protein, respectively. A central role of Aβ in the molecular pathology of AD has been established. Aβ is generated by sequential cleavages of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Under pathological conditions, Aβ self-aggregates to form Aβ oligomers, which likely induce abnormalities of tau and cause cellular stress responses, including caspase activation and disturbances of synaptic structure and plasticity. Thus, Aβ oligomers are considered to be an initiator of AD pathology.
The mechanisms by which Aβ oligomers induce neurotoxicity, critical issues from a therapeutic standpoint, remain to be elucidated, although several hypotheses have been suggested. The major theory is that extracellular Aβ oligomers interact with certain cell surface receptors to cause aberrant signal transduction. Alternatively, it has been suggested that extracellular Aβ oligomers disrupt the cell membrane directly or intracellular Aβ oligomers elicit neurotoxicity. Although a link between Aβ oligomers and tau has been established, signaling pathways linking the two remain elusive. It also remains to be clarified whether the neurotoxicity of Aβ oligomers is reversible and abates upon their removal. We previously established a primary neuron culture model in which Aβ oligomers trigger apparent neurotoxicity with relatively modest neuronal death. In the current study, we took advantage of this system to investigate the reversibility of Aβ oligomers-associated neurotoxicity, characterized by caspase activation and tau abnormalities. Here, we present evidence that the neurotoxicity of Aβ oligomers is reversible in primary neurons.
Our data showed that Aβ-O induces activation of caspase-3 and eIF2α, and abnormal phosphorylation and cleavage of tau. These abnormal alternations have been reported to be present in AD brains, suggesting that our model reflects the characteristic features of AD pathology. Our study also provides evidence of a direct link between Aβ oligomers and tau abnormalities, in accord with previous studies. To evaluate whether Aβ oligomer neurotoxicity is a reversible or irreversible process, we used an experimental paradigm in which neurons exposed to Aβ oligomers for 2 days were further treated with Aβ oligomers for 2 additional days or were deprived of Aβ oligomers for this same culture period. We then compared control and Aβ-oligomer-treated neurons on day 2, and control, Aβ-oligomer-treated and Aβ-oligomer-deprived neurons on day 4. We first focused on caspase-3 and eIF2α, both of which are thought to be important in mediating AD neurodegenerative processes. We found that the levels of cleaved caspase-3 and p-eIF2α in Aβ-oligomer-deprived neurons were much lower on day 4 than those in neurons continuously treated with Aβ oligomers, and were similar to those in controls. These findings suggest that neurons can recover following Aβ oligomer removal, even after neuronal injury responses to Aβ oligomers have already progressed, supporting the view that treatments targeting Aβ oligomers have significant therapeutic potential for AD.