The research quoted below is illustrative of a great deal of investigation into Alzheimer's disease and related amyloid biochemistry. There is a vast depth of detail remaining to be explored, even in areas thought to be comparatively well-mapped. While much of that exploration is business as usual, leading to expected destinations and anticipated confirmations, there is always the chance of upheaval, as might be the case here. Alzheimer's disease, like many neurodegenerative conditions, is characterized by the aggregation of solid deposits of misfolded or otherwise altered proteins in brain tissue: amyloid-β and phosphorylated tau. Once established, these deposits generate a complicated halo of surrounding biochemistry that is harmful to brain cells and their activities. In fact, pretty much everything to do with Alzheimer's disease is ferociously complex and nowhere near as well understood as researchers would like it to be.
Most efforts in Alzheimer's disease are presently directed towards ways to safely remove amyloid-β, with programs aiming to remove tau also underway. Removal has the advantage of needing less progress towards complete understanding of the biochemistry of the aged, diseased brain. Unfortunately even this shortcut has proven to be far more challenging than hoped. The past decade is littered with failed efforts to remove amyloid in the immunotherapy space, for example. Only very recently has success of any sort been demonstrated in human patients. The lack of tangible progress in amyloid clearance has spurred a great deal of exploration in the field, among researchers who believe that failure indicates not unexpected difficulty but that amyloid isn't the right target. There are dozens of newer theories on Alzheimer's disease floating around with varying degrees of support in the research community. So far this hasn't made much of a dent in the primacy of amyloid clearance efforts, but the clock is clearly ticking when it comes to the balance of funding and interest.
As is the case for many new discoveries in Alzheimer's biochemistry, the researchers use this one to suggest a different direction for the development of practical therapies. Here, the intent would be to replicate work from a related field and stabilize a precursor to amyloid, in theory preventing it taking the next step that produces the excess amyloid-β found in diseased brains. This isn't completely new in Alzheimer's disease research; inhibition of amyloid creation has been suggested as an approach at other stages along the road to amyloid formation. It isn't clear that there is any better evidence for effectiveness to date than there is for amyloid clearance, however. From a high-level perspective, if amyloid is the problem, then periodic removal should be a better class of therapy than continual suppression. This is only true if it can be made to work at all, of course.
It is a long-held belief in the scientific community that the amyloid-β plaques appear almost instantaneously. New infrared spectroscopy images, however, revealed something entirely different. The researchers could now see structural, molecular changes in the brain. "No one has used this method to look at Alzheimer's development before. The images tell us that the progression is slower than we thought and that there are steps in the development of Alzheimer's disease that we know little about. This, of course, sparked our curiosity." What was happening at this previously unknown phase? The results revealed that the amyloid-β did not appear as a single peptide, a widely held belief in the field, but as a unit of four peptides sticking together, a tetramer.
This breakthrough offers a new hypothesis to the cause of the disease. The abnormal separation of these four peptides could be the start of the amyloid-β aggregation that later turns into plaques. "This is very, very exciting. In another amyloid disease, transthyretin amyloidosis, the breaking up of the tetramer has been identified as key in disease development. For this disease, there is already a drug in the clinic that stabilizes the tetramers, consequently slowing down disease progression. We hope that stabilizing amyloid-β in a similar fashion may be the way forward in developing future therapies." The discovery could therefore alter the direction of therapy development for the disease. The aim of most clinical trials today is to eliminate plaques. Researchers will now try to understand the interaction patterns of amyloid-β preceding the aggregation process. Finding the antidote to whatever breaks the amyloid-β protein apart could open doors towards a major shift in the development of therapies for Alzheimer's disease.
Reducing levels of the aggregation-prone amyloid-β (Aβ) peptide that accumulates in the brain with Alzheimer's disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of Aβ. To date, the physiological state of Aβ in brain remains unclear, since the available methods used to process brain tissue for determination of Aβ aggregate conformation can in themselves alter the structure and/or composition of the aggregates.
Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of Aβ and amyloid precursor protein (APP) in the brains of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal Aβ aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of Aβ and APP that occur prior to plaque formation may provide novel targets for AD therapy.