Amyloid Precursor Protein Glycosylation is Different in the Alzheimer's Brain
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.
Hi there! Just a 2 cents.
''Unfortunately, lowering amyloid-β levels in the brain has failed to produce improvements in patients.''
If lowering did not improve things that much, it means there are other causative elements, not just amyloid junk accrual, most likley, inflammation and damage to neuron/they die and alzheimer's would accelerate the aging/possibly the epigenetic clock of the brain's various parts.
Off Topic: Incredible research from Spain (not kind of a surprise but now is confirmed in some people), atherosclerosis can happen so quickly, even inyoung age:
"This study is the first to analyze the progression of atherosclerosis at frequent intervals. The previous view was that the disease progressed very slowly throughout life. However, the new results show that the disease progressed **very rapidly in 40% of the individuals analyzed**."
Thus, nearly 1 out of 2 people (at least in that large-enough sample to make a concluision; of course, it would change - depending on the location - the diets of the people differ strongly by country/depending on their foods eaten, it can range from western macdonald diet all teh way to ethiopian tef and vegetarian 'bark eating') are having atherosclerosis, very rapidly. I was/am one of those 2; the one that got it. Thus you nearly have 1 chance out of 2 of getting it (in that sample). That's Huge odds to obtaining it. Now we know we see why so many (100s Millions of people) are affected by atherosclerosis, it's as deadly as cancer in terms of population disease weight/impact. Cancer can precipitate atherosclerosis, and likewise, in the inverse, atherosclerosis can precipitate cancer because it is dynsfunction of vasculature; thus this could haster vasculature related cancers (like blood cancer). It's not because you have atherosclerosis that necessarily you will get cancer (or vice versa too, but you arteries need to be pristine otehrwise it could happen), but these diseases can increase the (epi) mutational load/DNA mutations that end up deleterious and inflaammation causing, which can hasten cancer/rogue cell formation. Cancer is accelerated epigenetic aging (accelerated tumor suppressor arrivals which they suppress cell cycling to stop cancer formation by ROS destruction of cancers, likewise for immune killer cells/macrophages phaging cancers/eating them and producing ROS to destroy them (IL-6/Interferon-gamma/TNF-a), this can cause specific tissues to age faster or even 'systemically' (whole organs aging advancing, not just 'exclusively/locally in 1 organ only' but spread all over organs), thus cardiovasculature epiaging hastening; which can cause atherosclerosis or other CVD diseases.
Studies showed (by Horvath epiclock measuring clock of Many different organs' tissues, and also the Hannum clock on blood/saliva tissue) that indeed aging is not 100% the same in every organ, some organ age faster some slower; and 'aging/epiclock total' is the 'Average' of all the organs' varied DNA methylation epiages - combined/averaged (as done with Horvath's clock). That is the correct current full-body averaged epigenetic age of the person; but epigenetic aging can hasten in a Single organ (like say atherosclerosis) showing much more advanced epigenetic aging in the vasculature (it could likely be my thing, which I have now older arteries due to having had this disease, nearly 100% sure (I'm at risk to dying of atherosclerosis - later, even more), the only thing now is try to slow it down completely to a halt so it goes not further; since only Yamanaka/epi/splicing/transcription reprogramming can reverse the epigenetic age..until we can do that in vasculature, we have to slow it dramatically if it is now more advanced in its time - because 'playing catch up'/you have to do 2x efforts for the damage already incurred due to disease).
But the good thing, that studies showed, is that individuals/patients can serioulsy deviate later...as in the 'control' may age 'regularly' but they accelerate as they age - While The Patient who was more advanced in age - Did An Intervention and Halted the process and then, the Patient - Outlives - The control (much later on/decades later), maybe not that much since the patient was 'scarred' by the disease - but 'overcame it' 'just in time' while the aging process took course in the control (it was too late by then, it was just too progressive/slow and thus damage to permanent, decades later); although in Very Late States of a disease; it's nearly Too Late and death can come soon (Unless we build rejunvenation therapires soon that can Halt/Stop the process Dry and reverse time). But if Caufht Early Enough (especially in younger age) a disease can very slowed down (like in myself (I hope (for my life sake and for other's too who affliceted of such disease; no one wants to lose their life prematurely over a nearly uncureable disease)) and possibly, later, reversed; I mean it can only get worse - because Aging...but if you improve health; you give your chance to Age - Healthily; thus, you may 'offset' the aging process, to age healthily - enough/gracefully ; still age, but not die of the disease too soon. Such as when people die prematurely of the disease in much younger age.
And thus, once aging, 'staving off' the disease, coasting, gliding 'in enough health' and make sure your health is optimal (obviouslty it could be even better -if you never had that disease - but you had it, thus epigenetic mark(ed)/'signed/signature'/the epigenome was 'marked' by this event - but, Yamanaka reprogramming 'would erase' that diseaes event, it's whole point, to make it 'as if you never had that disease' in the first place, by erasing methylation/epiclock 'tab/mark' events of such event (kind of like erasing the stuff on your calendar (that was, and is to be) , as if it never happened/'Anew' calendar/clean(ed) slate; since the epiclock is that, ilke a epicalendar that keeps (past) tabs (methyls) of whatever dramatic event)). This was Proven (at least for this disease) with people that are Very Obese/Morbidly so, and lost like 500 lbs of weight...they are now healthy enough - but their epigenetics show something; they are epigenetically older/more damaged (despite now thin again) - due to that 'former damage' of being ultra over weight; so it's not inconsequential; there is 'mark' that is left to whatever hapepns (in the past) to your body (shown in epiclock). This can hasten or slow the epigenetic age of the person.
"Future data from [this] study will show whether this progression is associated with subsequent cardiovascular events. Until now, the speed of atherosclerosis progression has not been a factor in assessing individual risk."
It is.. associated, with cardiovascular events (I am living proof of it), I suffered debilitating cardiovascular ischemic, center chest stabbing knife pains and near-death events afterwards/of surviving (it) - due to it/atherosclerosis. The speed of progresion of it is a Major Factor.
Like many diseases, it is common sensical, that most, if accelerate, is bad news.
''Doctors often only detect atherosclerosis after a person has had a heart attack or stroke. At this late stage, interventions to reduce atherosclerosis have limited effectiveness.
Being able to detect atherosclerosis easily and knowing to look for it between the ages of 40 and 50 could, therefore, help stop the disease progressing to a point where it becomes dangerous.''
So true, prevention is Very protective...what you don't know might k*ll you ''ignorance is not always bliss''. Oftenly when doctors diagnose it, it's Too Late/Too advanced..because it is a 'silent killer/transparent' disease where you can feel No Pain whatsoever - and then, One Day, you feel pain like you never felt - from One Day (going perfectly well) to The Next (going completely bad) 'impromptu/by surprise'. Thankfully your company will defeat atherosclerosis usign rejuvenation. It must defeat the Last Stages/Advanced Stages of it, reversed at that late point (since most diagnosis Is At the point of no return/last advanced state before death).
''For Dr. López-Melgar, "The key finding of the study is that over a short follow-up of just 3 years, 40% of individuals aged between 40 and 50 years showed major progression of atherosclerosis in distinct locations, including the carotid, femoral, and coronary arteries."
"This rapid disease progression could make these individuals more vulnerable to developing symptoms or having clinical events, such as a heart attack or stroke."''
3 years......only, I would say it can take less than that; like a year or 2 in certain cases of much accerelated one.
Let me repeat - 3 years;
between 40 and 50 years old you can precipitously die once you have atherosclerosis.
Same thing with cancer, it can take 6 months to 5 years (some have cancer for decades but most it is short time), same thing alzheimers, after pre-alzheimer's, once you have it, it's downhill, and in 6 months you can become senile/demential/forget stuff as amyloid accumulate in your brain; and then death.
That is why the imperativity of solving aging (and diseases).
Just a 2 cents.
@CANanonymity The thing I just find ridiculous about AD studies involving amyloid beta is that they never include simultaneous removal of Tau. Proclara are trying that with GAIM, and I wish them luck. There are probably a couple of other things you could do to try to improve efficacy of GAIM further (I have a few ideas in that area myself, and i'm trying to get samples of GAIM to allow that research) - but I genuinely think that efforts which try to target Abeta without targeting Tau at the same time are just doomed from the start, even if Abeta is an important part of the disease.