Dysfunctional Maintenance in an Alzheimer's Disease Model Unexpectedly Results in Lower Levels of Amyloid-β
Cell biology is complicated, to say the least, and so the unexpected keeps occurring. Cell maintenance is carried our by a number of processes such as the ubiquitin-proteasome system (UPS) or the various forms of autophagy. Collectively these are responsible for clearing out broken structures and unwanted proteins within cells. There is plenty of evidence for the role of maintenance process of this nature in policing aggregates such as the amyloid-β associated with Alzheimer's disease. It is suspected that the faltering of autophagy that occurs with age is one the reasons why neurodegenerative conditions like Alzheimer's disease are a feature of late life only.
Here, researchers undertake a routine study of dysfunctional maintenance processes in Alzheimer's disease. They break the normal operation of proteasomal protein disposal via the use of mice with a mutant ubiquitin gene, and cross those mice with an Alzheimer's model lineage to obtain mice that exhibit both amyloid-β and broken clearance of molecular byproducts such as amyloid-β. The expected result was a much more rapid accumulation of amyloid-β, due to failure to clear unwanted protein aggregates, but in fact exactly the opposite occurred.
Sadly, the animal models of Alzheimer's disease are highly artificial constructs, as humans are near the only species in which this condition occurs. So it is hard to say whether this has any relevance to Alzheimer's disease in humans, or whether it is a peculiar artifact of the model. This has long been a major challenge in this field of research, the sizable gap between the animal models and the real thing, much larger than is the case for other conditions. It means that any new and promising result in animal studies should be only cautiously applauded, as all too many fail to go any further.
Deposition of extracellular amyloid plaques is one of the main pathological features of Alzheimer's disease (AD), the most common cause of dementia. These plaques are composed primarily of aggregated amyloid β-peptide (Aβ), which is generated through proteolytic processing of the amyloid precursor protein (APP) by β-secretases and γ-secretases. According to the "amyloid hypothesis", accumulation of Aβ in brain is the primary influence driving AD pathogenesis. Therefore, lowering Aβ is a major therapeutic goal in AD. This might be achieved by controlling the production, aggregation, or clearance of Aβ.
The ubiquitin-proteasome system (UPS) is a highly regulated mechanism for protein breakdown in cells. It has been put forward that impaired UPS-mediated proteolysis contributes to AD pathogenesis, but the significance of the UPS in Aβ metabolism remains largely unclear. To study the effects of a chronically impaired UPS on Aβ pathology in vivo, we crossed APPPS1 mice with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based UPS inhibitor. APPPS1 mice express a chimeric mouse/human mutant APP and a mutant human presenilin 1, mutations that both represent early-onset AD, in central nervous system neurons and develop β-amyloid deposits in brain. Unexpectedly, the APPPS1xUBB+1 crossbred mice showed a decrease in plaques during aging. Also, levels of soluble Aβ42 were reduced in brain, suggesting that lower levels of Aβ42 might contribute to the decreased plaque load.
To investigate the effects of UBB+1 expression on APP processing, we carried out secretase activity measurements on brain tissue samples from different mouse lines. In APPPS1 mice, a partial decrease in γ-secretase activity was found compared to wild-type mice, in agreement with disruption of normal γ-secretase function. Interestingly, in APPPS1xUBB+1 triple transgenic mice, γ-secretase activity was partially restored, specifically at 6 months of age. Onset of amyloid plaque pathology in the APPPS1 mouse model occurs at approximately the same age. How UBB+1 exerts this stimulating effect on γ-secretase is not clear, but a potential mechanism may involve regulation of presenilin expression.
And there is the fundamental issue of whether AB is a cause of Alz, or just a curious byproduct or marker
While your posts are a great service to the community, we all occasionally make errors, and you made an error here.
The ubiquitin-proteasome system (UPS) is not 'autophagy.'
It's a totally distinct system for clearing proteins, whereas autophagy can degrade every macromolecule and organelle. When the UPS fails, autophagy can increase to compensate. The systems are linked but quite different.
As someone who is quite optimistic about the prospects of autophagy enhancement in neurodegenerative disease, I would feel a bit better if you corrected the article to replace 'autophagy' with UPS.
Indeed, I don't really believe that blocking the UPS will help with AD or any other (alleged) proteopathy.
All of the evidence before this paper indicates that improper function of the UPS will only accelerate aging. This study featured a very contrived model, as nearly all AD models are (with the exception of the APOE4/4 mouse -- which takes too long to develop 'dementia' and so the community largely ignores it in favor of contrived APP and secretase models).
I would not draw conclusions from such an artificial and physiologically unrealistic model. Even if A-beta is causal in *sporadic* AD, which is exceedingly unlikely, the level of A beta pathology in the APPPS1 mouse is just off the chart.
@Sebastian Aguiar: Thank you; the perils of writing in bulk late at night. The post is corrected.