How Reversible is the Cellular Dysfunction Related to Amyloid-β?

This is an interesting experiment, though note that the DOI link goes straight to a PDF at the time of writing. It is carried out in cell culture, so don't take the results too seriously: they would have to be replicated in at least an organoid tissue structure that better matched natural brain tissue. Nonetheless, the researchers show that brain cells in this more artificial environment are capable of recovering from some of the damage done by the presence of amyloid-β, the protein aggregate associated with Alzheimer's disease. The present consensus is that it isn't the amyloid itself that causes the harm, but rather the surrounding halo of related proteins and fragments. Still, get rid of the amyloid, and that halo vanishes as well.

Patients with Alzheimer's disease (AD) chiefly suffer from impairment of memory and other cognitive functions. AD is neuropathologically characterized by senile plaques and neurofibrillary tangles, which are composed of amyloid β-protein (Aβ) and phosphorylated tau proteins, respectively. Recently, a new concept has emerged: that soluble oligomeric forms of Aβ (Aβ oligomers), but not Aβ fibrils, play a primary pathogenic role in the pathological cascade of AD. This idea is based on findings that soluble forms of Aβ provoke neurotoxic effects, including tau abnormalities (especially hyperphosphorylation), functional and structural abnormalities of synapses, and induction of neuronal death. This concept is supported by numerous studies that have employed a variety of experimental systems, including cell culture, brain slices, and animal models, as well as the fact that Aβ oligomers are abundant in post-mortem AD brains. Thus, oligomeric Aβ is considered a major culprit in the molecular pathology of AD.

To investigate the pathological roles of Aβ oligomers, we have established a neuron culture model system, in which rat primary neurons are exposed to relatively low concentrations of Aβ42 oligomers (Aβ-O) for relatively long periods (2-3 days). We observed that Aβ-O induces neurotoxic insults with limited cell death under these conditions. Because these changes are reflective of characteristic pathological features of AD, this neuron model is considered a useful system for investigating the neurotoxic mechanisms triggered by Aβ oligomers.

We were interested in the question of whether the neurotoxicity of Aβ oligomers is reversible and abates upon their removal, an issue that has remained largely unexplored. To investigate this possibility, we designed the following experimental paradigm: Rat primary cultured neurons were treated with Aβ-O for 2 days, at which point cells were deprived of Aβ-O by replacing the medium with fresh medium lacking Aβ-O, or were re-provided Aβ-O and cultured for an additional 2 days; untreated neurons were used as controls. Neurons continuously treated with Aβ-O showed greater activation of caspase-3 and eIF2α, and exhibited persistent, abnormal alterations of tau and β-catenin. In contrast, upon Aβ deprivation, caspase-3 and eIF2α activation were considerably attenuated, aberrant phosphorylation and caspase-mediated cleavage of tau recovered for the most part, and abnormal alterations of β-catenin were partially reversed.

These results indicate that removal of extracellular Aβ-O can fully or partially reverse Aβ-O-induced neurotoxic and synaptotoxic alterations in our neuron model. Our findings suggest that Aβ oligomer-associated neurotoxicity is a reversible process in that neurons are capable of recovering from moderate neurotoxic insults. These data also support the idea that Aβ oligomers act on the cell surface of neurons to transmit aberrant signals, resulting in various abnormal cellular responses; upon Aβ oligomer removal, the aberrant signals subside, resulting in reversal of all abnormal responses.



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