A Potentially Useful New Finding in the Biochemistry of Amyloid-β

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.

Never before seen images of early stage Alzheimer's disease

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.

Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP

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.


Agree that this seems a much less promising approach than just getting rid of the Amyloid Beta clumps.

I'd love to see a non IgG antibody approach (presumably non inflammatory, non ARIA causing) to removing the clumps such as the SENS sponsored research on IgM antibodies to AB or the creation of a protease targeting it.

Given that Michael has pointed out that IgM antibodies against AB have already been demonstrated in an in vivo model, I don't know what the pharma industry is waiting for?

Posted by: Jim at March 13th, 2017 6:49 PM

Re reading that previous paper, I see they used a gene therapy to generate the IgM antibody in vivo:

"We previously isolated Aβ-specific catalytic antibody, IgVL5D3, with strong Aβ-hydrolyzing activity. Here, we evaluated the prophylactic and therapeutic efficacy of brain-targeted IgVL5D3 gene delivery via recombinant adeno-associated virus serotype 9 (rAAV9) in an AD mouse model. One single injection of rAAV9-IgVL5D3 into the right ventricle of AD model mice yielded widespread, high expression of IgVL5D3 in the unilateral hemisphere. IgVL5D3 expression was readily detectable in the contralateral hemisphere but to a much lesser extent. IgVL5D3 expression was also confirmed in the cerebrospinal fluid. Prophylactic and therapeutic injection of rAAV9-IgVL5D3 reduced Aβ load in the ipsilateral hippocampus of AD model mice. No evidence of hemorrhages, increased vascular amyloid deposits, increased proinflammatory cytokines, or infiltrating T-cells in the brains was found in the experimental animals. AAV9-mediated anti-Aβ catalytic antibody brain delivery can be prophylactic and therapeutic options for AD."

Maybe wild woman Liz Parish could try this on an Alzheimer's patient down in Colombia. It looks like it could do more for Alzheimer's than telomerase gene therapy.

Posted by: Jim at March 13th, 2017 6:53 PM

I'm not an expert on AD, but what has struck me of the things I heard so far:

An expert stating that AD in its early stages isn't distributed evenly in the brain, but rather resembles an infection-like progression starting from the first cranial nerve (olfactory nerve). I'm not sure how that can be reconciled with a genereal misfolded protein accumulation, which is not expected to have a preferential site.

The notion that Aβ aggregates are immunologically active. Also it has been shown that the blood-brain barrier gets more leaky with age. Is it possible the brain is trying to defend itself with those aggregates from particles intruding the brain (they don't have to contain DNA by the way). Can anyone assess how likely this is?

I'm more concentrated on other aging mechanisms myself, because neurodegenerative diseases seem too complicated for me and one had to concentrate on them solely.

Posted by: K. at March 14th, 2017 3:33 AM

We prior to 2000, demonstrated biochemical changes with AD before any prodromal or incubation stages. Its good to know that in this protracted disease something is found to support our hypothesis decades later. This doesn't eliminate the role of hallmark lesions but reiterates that something happens much earlier than stages when lesion appear. BTW Alois Alzheimer didn't have the disease that bears his name, so Its Alzheimer disease or Alzheimers even, but not Alzheimer's disease to be correct.

Posted by: Dr. Obrenovich at March 19th, 2017 6:28 PM

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