Does the cerebral spinal fluid of people with Alzheimer's have a notably different pH from 'normal' people's?

Submitted by wrhollin t3_yfothk in askscience

Hello all! Bit of background: I'm a physical chemist by training, and did my doctoral work on self-assembly in conjugated polyelectrolytes. In that field there are open questions about how things like temperature, pH, salt content drive and control self-assembly and processes like liquid-liquid phase separation. I recently came across this article discussing liquid-liquid phase separation of Tau. I have very marginal knowledge of the state of Alzheimer's research and whether the various hypotheses regarding plaque aggregation are causal or symptomatic. So I'd like to know more about whether the CNS of folks with Alzheimer's varies significantly in its pH and electrolytic balance vs a normative sample of CNS.

For the record: I'm no longer in academia (although I still have journal access) and my industry is semiconductors, not biomedical. So I'm not fishing for competitive advantage in this field.

Cheers, and thank you.

2,473

Comments

You must log in or register to comment.

FlowersForAlgerVon t1_iu4z5bb wrote

I can weigh in since I'm in the field. You don't generally see pH differences in the cerebral spinal fluid, our body does a pretty good job at regulating it. You DO see differences in pH in the cell, i.e. lysosome is about pH 4.6 and cytosol is about pH 7.2. Tau and beta amyloid protein do experience a range of pH environments. One of the hypothesis for the spread of tau is through the process of endocytosis, wherein a neuron that contains tau tangles may die and release the tau, then an adjacent neuron creates a pouch that internalizes outside contents (including tau proteins). This pouch becomes an endosome which becomes acidic in nature.

On the topic of the causation or symptom, it is unclear, but we do know there is a positive feedback loop. In clinic trials, we've gone after Abeta plaques, but these drugs show limited efficacy (Aducanumab is an FDA approved antibody that clears Abeta plaques, but again limited efficacy).

​

In terms of CSF tests, there are some biomarkers being looked at right now that include soluble Abeta oligomers, hyperphosphorylated tau, even certain enzymes. Though the way they diagnose AD generally is by ruling out other dementias, and then brain scans.

704

wrhollin OP t1_iu52b9f wrote

Hi thanks for the response. Do Tau and Abeta have charged surfaces? Are their surface charges different in healthy versus diseased brains?

131

FlowersForAlgerVon t1_iu5e8ax wrote

No problem, happy to answer your questions! Tau and Abeta are rather complex proteins that have amino acid residues that carry charges allowing it to take certain shapes. The pathogenic form of tau is the hyperphosphorylated version, where tau carries more phosphate groups (negatively charged) allowing it to stick to each other and form what we call neurofibrillary tangles inside a neuron. How the ionization states and interaction with itself is affected by pH environments, I've no clue. For Abeta, the larger protein has been shown to more readily form these plaques due to a larger surface area, I'm not sure how ionization states affect the formation there either.

​

That's about the best I can answer your question haha.

​

Edit: Tangentially, the pH environment can affect enzyme ionization states that changes the shape enough that it increases production of these 'large' Abeta oligomers, leading to more accumulation of plaques.

144

notjeffre t1_iu7gab6 wrote

that little bit you mentioned about the effect of pH environment on the ionization & interaction of disordered proteins is exactly what I’ve been working on for my biophysics phd research lol

(not tau, but another intrinsically disordered protein. its not often I see the last five years of my life succinctly mentioned in a single sentence on my reddit scroll)

48

PyroDesu t1_iu7rkq1 wrote

> The pathogenic form of tau is the hyperphosphorylated version, where tau carries more phosphate groups (negatively charged) allowing it to stick to each other and form what we call neurofibrillary tangles inside a neuron.

What causes the hyperphosphorylation, out of curiosity?

5

Carl_The_Sagan t1_iu5mhv0 wrote

Yes actually , both tau and amyloid can be phosphorylated which gives them negative charge

15

ScienceIsSexy420 t1_iu6mtix wrote

Very interesting. I'm curious, do you know what's the proposed mechanism is for tau proteins and CTE? Is the idea that the concussions cause cellular death, resulting in the spreading of tau proteins via invagination?

3

TheFencingJared t1_iu72p6o wrote

I believe that the current theory holds that it's likely a result of a lot of different things. One big mechanism we're learning about is dysregulated TDP-43, which is an RNA-binding protein that regulates tau and is involved in ribosome metabolism. Abnormal TDP-43 pathology has been found in a ton of cases of CTE, including cytoplasmic neuronal inclusions, neurites, and glial inclusions. In mouse models, TBI has resulted in upregulation of TDP-43, and in diseases associated with odd TDP-43 metabolism, tau metabolism is often altered too.

That being said, there are probably tons of other factors, and how p-tau is able to make more p-tau after neurons die and spill it out (or after it's transported out of neurons like trash) is still under investigation

9

I4Vhagar t1_iu7wmu6 wrote

Side question, what’s happening biologically when a patient begins to “sundown”?

Worked geriatrics for 2 years and it was like clockwork with certain folks. I always assumed it was issues with signals in the pituitary

3

Orange-Enough t1_iu8tjlf wrote

It looks like there's no definitive pathophysiology of sundowning, but several evidence-based hypotheses as to why it likely occurs.

TL;DR: parts of the brain effecting circadian rhythms, behavioral regulation, and stress response are changed/damaged. Environment and fatigue can also play a role.

According to Canevelli et al., 2016:

Sundowning could caused by a disruption in circadian rhythm due to alteration of the suprachiasmatic nucleus (SCN), basically the "pacemaker" of circadian rhythyms, located in the hypothalamus (forebrain). This naturally degenerates with age, but damage to this area is seen even more so in people with AD, as noted by neuronal loss and accumulation of neurofibrillary tangles.

In severe AD, the SCN also shows reactive gliosis (the universal response to brain injury) in response to neuronal loss, with an increase in the astrocyte/neuron ratio. Essentially, a physiological response to brain injury in the hypothalamus interfering with regulation of sleep and emotional activity.

Additionally, circadian rhythms are regulated by melatonin, secreted by the pineal gland in response to darkness. The pineal gland's Melatonin functions are regulated by the SCN (which we know is damaged in AD). Melatonin is usually greatly reduced in people with AD, effecting circadian rhythms.

"Another possible cause is the degeneration of the cholinergic system. The SCN receive several cholinergic projections arising from the cholinergic forebrain and brain stem nuclei. Moreover, it is sensitive to cholinergic stimulation as demonstrated by the expression of muscarinic acetylcholine receptors both in SCN neurons and astroglial cells. Thus, it may be hypothesized that the impaired cholinergic transmission may contribute to the disruption of circadian rhythms and the emergence of behavioral disturbances" (Canevelli et al., 2016)

Another hypothesis is disruption/dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. In several studies, people with AD showing sundowning had significantly higher cortisol levels (stress response, regulated by HPA) than those without sundowning.

Lastly, environmental impacts such as decreased light exposure during the day (in a facility), fewer staff in late afternoon/evening, fatigue, and changes to or absence of daily routine have been associated with an overall worsening of NPS and the emergence of sundown syndrome

3

DudoVene t1_iu4hu5o wrote

notably : no. pH in physiological fluids in mammals is very stable and involves many biochemical process in order to. for example, blood pH roughly vary for less than 0.2 ph unit in normal conditions. Any larger variation in this value will lead to conformationnal changes in circulating proteins and also on exhibited proteins (like receptor on the cell surface) and finally strong metabolic issue.

198

Existing_Thought5767 t1_iu4nofz wrote

This is the right answer. pH should not change in your body unless you have some really serious problems. Even pH in water is relatively consistent when talking about bodies of water. If pH drops in water then it leads to coral bleaching and kills off living things that would need a stable pH. Many things adapt to the pH in their environment.

49

ELI-PGY5 t1_iu4vi1s wrote

It’s not really the right answer. Because we test the pH of bodily fluids pretty regularly, and it’s clinically useful. Just not useful in CSF in standard practice, and it definitely not a standard test in Alzheimer’s.

25

NergalMP t1_iu536tk wrote

It’s clinically useful because pH outside the normal range is indicative of a significant problem. Mammalian physiology operates in a pretty narrow pH range with many processes maintaining it.

28

ELI-PGY5 t1_iu56p3o wrote

  1. pH changes in bodily fluids are often clinically useful
  2. I don't really care about pH in CSF.
  3. I doubt it's a good test for Alzheimers, as we would presumably all be doing it if a $20 investigation could detect the condition. The linked article isn't very relevant to everyday clinical medicine.
12

NergalMP t1_iu5l91f wrote

Sorry, I meant it can be clinically useful outside the specific CSF/Alzheimer’s question. I’m sure it’s irrelevant to that.

7

MeshColour t1_iu54qhd wrote

We test blood oxygen level pretty regularly too, which is also clinically useful?

That's unrelated to the fact that for a healthy person that it should not vary

13

Existing_Thought5767 t1_iu5gzml wrote

It is 100% the right answer. Just because you are checking pH in blood doesn’t mean it suppose to change when you get sick or something. As people in this have said .2 pH is the most change you will see in the human body, anything more than that change you body literally cannot function. Cells would be destroyed very quickly.

−3

ELI-PGY5 t1_iu5i898 wrote

That’s gibberish. pH of blood changes in specific disease states. Checking blood pH is a common, useful pathology test.

As for 0.2 = “cells destroyed very quickly” “body would literally not function” - you’re exaggerating. A drop of 0.2 (7.4 to 7.2) would not even count as a severe acidosis.

So I rate your comment 3.2% the right answer, not 100%.

10

Daguvry t1_iu5zvmw wrote

Run blood gases all the time working in Respiratory. That's how we monitor correct vent settings and most COPD patients on BIPAP. I can swing blood pH by more than .2 in less than hour with tidal volumes and respiratory rates.

Out of control diabetics can get really low pH values but that's a metabolic issue, not a respiratory issue. I've seen plenty of diabetics under 7.0 pH where the normal pH values are 7.35-7.45

5

ELI-PGY5 t1_iu7lm1h wrote

Yeah, I was think of a guy I saw recently with DKA, pH 6.9, not crisp but his cells were also not all dead.

5

gasdocscott t1_iu8ox4x wrote

I've treated patients with pH less than 6.7 (or lower- the gas machine doesn't go lower). Often DKA, which is remarkably responsive to treatment even at those extremes.

1

DidjaCinchIt t1_iu4xwvz wrote

People: “But, but, but what about alkaline water? It’s good for you!”

Stomachs: LULZ

33

minion_is_here t1_iu7981d wrote

That's kind of a separate issue. Chronic acidosis is a big problem in the U.S. (probably due to our diets + stress), so you may say the stomach's self-regulation will always keep the proper pH, that is just not true. Alkaline water doesn't treat the root cause, though. It may help some people with symptoms because it's like taking a weak antacid. You could probably get a better result with tums.

6

fastspinecho t1_iu5aua4 wrote

That doesn't really answer the OP's question.

It's entirely possible that pH is both "stable" (i.e. small standard deviation in normal people) AND significantly different in Alzheimer's.

In fact, the more "stable" it is normal people (i.e. the smaller the standard deviation), the smaller a change needs to be in order to be significantly different in Alzheimer's.

For example, if all healthy people have pH between 7.36 and 7.44, then pH of 7.33 would be evidence of pathology.

That said, I don't believe there is any good evidence that the pH of CSF is significantly in Alzheimer's and controls.

13

ELI-PGY5 t1_iu4v6gs wrote

The normal range for pH is 5 times that. And we see sick or sick-ish people outside that range pretty regularly. Pretty much everyone at my local hospital who gets blood drawn gets their pH checked.

But as to OPs question - my answer is no. We don’t have any simple tests for Alzheimer’s. MRI and PET provide decent info. But if pH on an LP was different, we’d suddenly have a simple, cheap-ish test for the condition.

pH isn’t a useful test on CSF in normal circumstances btw. We do care about pH in other fluids - pleural fluid, vaginal samples, blood etc.

−3

mirrim t1_iu4wf9y wrote

This is not true. Normal blood pH is 7.35-7.45. A pH of 6.4 or 8.4 would be fatal. The instruments in my lab can't even read lower than 6.8.

21

Grogfoot t1_iu50dpc wrote

"Fluids" is pretty broad, and would include things such as urine, which can be quite variable. But, OP and the thread is referring to fluids that would likely be those continuous with blood and would definitely not vary by an entire pH unit!

Typical pH values of blood are ~7.3. A blood pH less than 6.8 wouldn't even be incompatible with life let alone "normal range".

14

ELI-PGY5 t1_iu5ei09 wrote

Sorry, it’s 2am and I misread. The guy I was responding to is too high not too low. Normal range for blood pH is .1 unit, I would disagree that pH varies by 0.2 in normal conditions, 7.2 to 7.4 is a pretty massive difference as you presumably know.

But that’s largely irrelevant to my point, which is that pH is not so stable that it can’t be used for diagnostic purposes. It’s just that it’s not used for the diagnostic purpose that the OP asked about, and the behaviour of tau proteins etc as noted in the reference doesn’t lead me to think that it is likely to be.

5

Megalomania192 t1_iu4usf0 wrote

>Does the cerebral spinal fluid of people with Alzheimer's have a notably different pH from 'normal' people's?

Probably not, but not for the reasons others have stated (which are true).

Excess Tau Protein in the CSF is the only reliable assay test we have for Alzheimers, because the Tau protein escapes into the CSF, but Alzheimers isn't a disease of the CSF. Alzheimers is a disease of Neuron Cells in the Brain.

The better question might be - is the Neuronal pH of Alzheimers disease patients different from nominally health people?

I also don't know the answer to this question either, but you might be able to find out. I wouldn't expect there to be a global difference in pH - homeostatis is very effective and long term pH changes are make for very unhappy cells (i.e. necrosis and death), but whether the pH changes during acute stress events enough to make a difference is an interesting thought that someone may have pursued.

13

ZockerTwins t1_iu6lhrz wrote

This is so cool. I just finished my Bachelors thesis in physical chemistry and the group I was in also worked on liquid-liquid pase transistions of polyelectrolytes. They investigated the effect of salt concentrations with Raman microscopy. I know this isn't an AMA, but I have one question for you: What made you leave academia and go into industry? Was it always you goal?

10

Applejuicyz t1_iu6f0i3 wrote

Hi! I do research into protein aggregation and LLPS (liquid-liquid phase separation). Other people have already mentioned that pH isn't that different, so I'd like to elaborate on the phase separation. It's unlikely that tau phase separates itself without other components (simple coacervation), but rather complexes with more molecules (complex coacervation). Because of this, LLPS can be triggered through concentration of either component or other solutes present in the cell, or perhaps even by the presence of sequence specific proteins/RNA.

Furthermore, currently the oligomeric, soluble species are being pointed at as the main toxic species. This is not to say that the fibers don't have a role in disease progression (perhaps through spreading and fragmentation), just that they carry less toxic effects than the oligomers.

There's also the liquid-to-solid transition that's bejng discussed at the moment in literature, or my favourite, a pathway in which pre-existing LLPS compartments can influence and trigger protein aggregation.

Disclaimer: written after 12, so may contain some inaccuracies!

8

stupidshinji t1_iu4stab wrote

This is something a professor at my school studies, but I have a comparable research background to yours. From what I understand pH does play a role in aggregation and fiber formation, but it likely the stomach/GI tract where this matters as it’s the only place with drastically different pH.

6

vertex79 t1_iu6dpqt wrote

Urine pH can vary pretty wildly. Usually 6 to 7 but I've seen as high as 9 and as low as 5. I'm only measuring it for the purpose of sample preservation prior to other analysis but it is available in our lab as a diagnostic measure, usually related to stone formation. Blood pH also varies as others have said due to respiratory and metabolic issues.

6

stupidshinji t1_iu6gg2u wrote

Interesting I didn’t know pH could vary that much for urine. From the research on OPs question i’ve seen it’s a pH of four or lower that causes the aggregation so thankfully it’s not as likely be induced in other parts of the body.

3

vertex79 t1_iu6qr5w wrote

Well I don't think pathological protein aggregation is anything to do with CSF pH. The CSF is not bathing the individual cells. CSF surrounds the brain and performs various functions. Within the mass of the organ the gaps between cells are filled with interstitial fluid. These are not the same.

Edit: there are protein aggregation diseases that are systemic and rather horrible. These are bundled together under the term amyloidosis. These do not involve the "amyloid" protein involved in alzheimers disease, rather a diverse range of proteins that aggregate for various reasons. The alzheimers amyloid protein was lumped into this historically. This was because it was recognised that protein clumping was a common feature as amyloid plaques were easily visible histologicaly because they show birefringence under Congo red staining.

These are different diseases from alzheimers but bear in mind that most neuro degenerative diseases involve some form of abnormal protein aggregation, from alpha synuclein in parkinsons to the poly-CAG-opathies such as Huntington disease.

4