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Amyloid Precursor Protein Glycosylation is Different in the Alzheimer's Brain

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Posted 25 September 2020 - 08:20 PM

The puzzle of Alzheimer's disease is why it only occurs in some people. Unlike other common age-related diseases, such as atherosclerosis, it isn't universal, even in groups exhibiting all of the lifestyle risk factors. Thus a strong theme in the Alzheimer's research community is the search for clear and robust differences in cellular biochemistry between people with and without the condition, in an attempt to shed more light on how and why Alzheimer's arises.

In the absence of a complete understanding of how and why Alzheimer's disease begins, the strategy for developing effective therapies is haphazard. Perhaps the obvious points of intervention based on today's knowledge are good, perhaps not. The history of this research and development is not encouraging. Most past work has focused on clearance of amyloid-β aggregates, an obvious point of difference between diseased and normal brains, informed by the amyloid cascade hypothesis. Unfortunately, lowering amyloid-β levels in the brain has failed to produce improvements in patients.

Back to the question of why only some people suffer Alzheimer's disease: a good deal of theorizing has taken place to try to explain this observation. For example, perhaps Alzheimer's disease is primarily driven by maladaptive responses to persistent infection, such as by herpesviruses. This is a state that occurs in a sizable fraction of the population, but not in everyone. There is as much digging into cellular biochemistry as theorizing, however. Today's open access research materials are a good example of this part of the search for differences between Alzheimer's patients and healthier old individuals, in that the focus is on cellular biochemistry. Only later would there be efforts to try to connect this difference to causative mechanisms.

New alteration in the brain of people with Alzheimer's discovered

Despite the important advances in research in recent years, the etiopathogenesis of Alzheimer's disease is still not fully clarified. One of the key questions is to decipher why the production of beta amyloid, the protein that produces the toxic effect and triggers the pathology, increases in the brain of people with Alzheimer's. The research has focused on the different fragments of the Amyloid Precursor Protein (APP) until now, but the results have been inconclusive, because this protein is processed so quickly that its levels in the cerebrospinal fluid or in the plasma do not reflect what is really happening in the brain.

Glycosylation consists of adding carbohydrates to a protein. This process determines the destiny of the proteins to which a sugar chain (glycoproteins) has been added, which will be secreted or will form part of the cellular surface, as in the case of the Amyloid Precursor Protein (APP). The alteration of this glycosylation process is related with the origin of various pathologies. In the specific case of Alzheimer's, the results of the study suggest that the altered glycosylation could determine that the APP is processed by the amyloidogenic (pathological) pathway, giving rise to the production of the beta-amyloid, a small protein with a tendency to cluster forming the amyloid plaques characteristic of Alzheimer's disease.

The fact that the glycosylation of the amyloid precursor is altered indicates that this amyloid precursor may be located into areas of the cell membrane that are different from the usual, interacting with other proteins and therefore probably being processed in a pathological way.

Amyloid precursor protein glycosylation is altered in the brain of patients with Alzheimer's disease

In this study, elevated APP mRNA expression was found in the brain of Alzheimer's disease (AD) subjects when compared to non-demented controls (NDC) individuals. Several studies have already reported increases in expression of total APP mRNA, both considered as a whole. However, there is contradictory data regarding APP mRNA expression in the brain of AD patients, with several reports indicating no change or weaker expression. In conclusion, it remains unclear if brain-specific regional and temporal changes occur in the expression of the different APP variants during AD progression. Since APP is also found in blood cells, assessing the changes in APP mRNA expression in peripheral blood cells from AD patients has been considering an alternative. However, again the quantification of APP mRNA in peripheral blood cells has generated controversial results.

Brain APP protein has been analyzed in only a few studies, probably as it is difficult to interpret the complex pattern of APP variants and fragments. We previously characterized the soluable APP (sAPP) species present in the cerebrospinal fluid (CSF), which form heteromers involving sAPPα, sAPPβ, and also soluble full-length forms of APP. Our approach allows the sAPPα and sAPPβ species derived from APP695 and APP-KPI to be studied separately. Here, we found a similar balance of sAPPα and sAPPβ protein, and of that between C-terminal fragments CTFα and CTFβ, in brain extracts from AD and NDC subjects. Interestingly, despite the lack of any differences between NDC and AD patients, the ratio of APP695/APP-KPI species was associated with very different profiles of sAPPα and sAPPβ. Our results indicate that relevant amounts of sAPPβ are likely to be generated in non-neuronal cells and that their pattern of glycosylation may serve to characterize changes in AD.

Moderate changes in the glycosylation of key brain proteins may critically affect their behavior. Alterations to the glycosylation of specific glycoproteins may alter the contribution of different cell types to the protein pool, producing an imbalance in protein glycoforms, and such altered glycosylation may reflect changes in metabolism or in differentiation states. In this context, the altered glycosylation of APP in AD warrants further study, particularly as we assume that APP glycosylation determines its proteolytic processing. As such, alterations to its glycosylation may have pathophysiological consequences in terms of the generation of the diverse APP fragments.

View the full article at FightAging

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