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.


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.