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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).

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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.

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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?

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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.

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

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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.

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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)

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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?

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Carl_The_Sagan t1_iu5mhv0 wrote

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

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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?

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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

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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

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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

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