In recent years, researchers have made a number of major advances in understanding the origins of Alzheimer’s. But a new study shows that however much we know, new studies can change the game.
The prevailing theory of Alzheimer’s suggests that the destructive buildup of plaques outside brain cells occurs because brain cells secrete too much beta-amyloid peptide, the precursor to plaques. Recent studies have suggested that the problem in Alzheimer’s lies not in the brain’s production of the plaques, but in its clearance of them.
There is some level at which the cell can no longer hold the beta-amyloid that accumulates within it, so the membrane may burst, expelling beta-amyloid peptide into the extracellular space. It is at this point that beta-amyloid can turn into full-blown plaques outside the cells.
However, there may be even more to the story than what we knew up till now. New research shows that brain cells may actually have trouble secreting beta-amyloid peptide that has built up inside the cells, rather than secreting too much. The team showed that beta-amyloid builds up within the neuron first, presumably because the neuron has trouble pushing it out. And it’s this early step – the internal buildup of the beta-amyloid – that may be the cornerstone of the disease.
Study author Gunnar Gouras suggests that pharmaceutical companies may need to take the findings into account as they design Alzheimer’s medications. "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.”
The reason for the cells’ inability to rid themselves of beta-amyloid is unclear, but author Davide Tampellini says that it 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.” Future studies will need to look into the exact reasons the pathways begin to malfunction. This, finally, may get to the root cause of why Alzheimer’s develops at all.
The study was carried out at Weill Cornell Medical College and published in the October 26, 2011 online issue of the Journal of Neuroscience.
