Conventional wisdom has been turned on its head in Alzheimer's research. It is now posited that reduced secretion of beta-amyloid could signal the onset of the disease, not increased secretion. The Swedish discovery, when further confirmed, could spell a new direction in the treatment of the disease that poses a great challenge the world over.
For decades the amyloid hypothesis has dominated the research field in Alzheimer's disease. The theory describes how an increase in secreted beta-amyloid peptides leads to the formation of plaques, toxic clusters of damaged proteins between cells, which eventually result in neurodegeneration.
But now scientists at Lund University, Sweden, are presenting a radically different explanation. The research group's data offers an opposite hypothesis, suggesting that it is in fact the neurons' inability to secrete beta-amyloid that is at the heart of pathogenesis in Alzheimer's disease.
The study by researchers with Scientists at Lund University shows an increase in unwanted intracellular beta-amyloid occurring early on in Alzheimer's disease. The accumulation of beta-amyloid inside the neuron is here shown to be caused by the loss of normal function to secrete beta-amyloid.
Thus contrary to the dominant theory, where aggregated extracellular beta-amyloid is considered the main culprit, the study instead points to reduced secretion as the key factor.
The findings are, published in the October issue of the Journal of Neuroscience
Professor Gunnar Gouras, the senior researcher of the study, hopes that the surprising new findings can help push the research field in a new direction.
"The many investigators and pharmaceutical companies screening for compounds that reduce secreted beta-amyloid have it the wrong way around. The problem is rather the opposite, that it is not getting secreted. To find the root of the disease, we now need to focus on this critical intracellular pool of beta-amyloid.
"We are showing here that the increase of intracellular beta-amyloid is one of the earliest events occurring in Alzheimer's disease, before the formation of plaques. Our experiments clearly show a decreased secretion of beta-amyloid in our primary neuron disease model. This is probably because the cell's metabolism and secretion pathways are disrupted in some way, leading beta-amyloid to be accumulated inside the cell instead of being secreted naturally", says Davide Tampellini, first author of the study.
The theory of early accumulation of beta-amyloid inside the cell offers an alternate explanation for the formation of plaques. When excess amounts of beta-amyloid start to build up inside the cell, it is also stored in synapses. When the synapses can no longer hold the increasing amounts of the toxic peptide the membrane breaks, releasing the waste into the extracellular space. The toxins released now create the seed for other amyloids to gather and start forming the plaques.