Brain aging: Evaluation of pH using phosphorus magnetic resonance spectroscopy

Cichocka, Monika; Kozub, Justyna; Urbanik, Andrzej

doi:10.1111/ggi.13272

Cited by 4 publications

(2 citation statements)

References 17 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These data imply that one possible reason for the divergent fibrillization of tau in Alzheimer's and CTE disease on one hand, and Pick's disease on the other hand, may be the difference in the environment's pH. Interestingly, tau pathology in Alzheimer's initially spreads from entorhinal cortex and locus coeruleus to the hippocampus (Goedert et al, 2017), and there are reports to suggests that the pH in the left hippocampus of Alzheimer's patients does increase rather than decrease in the age-related manner (Mecheri et al, 1997; Mandal et al, 2012; Cichocka et al, 2018). In contrast, the assembly of tau prions in Pick's disease would presumably be facilitated by a moderate drop in pH that accompanies e.g., transit in the endosomal system, inflammation response or an ischemic injury.…”

Section: Resultsmentioning

confidence: 99%

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

Cieplak

2019

Front. Neurosci.

View full text Add to dashboard Cite

Tau-related dementias appear to involve specific to each disease aggregation pathways and morphologies of filamentous tau assemblies. To understand etiology of these differences, here we elucidate molecular mechanism of formation of tau PHFs based on the PMO theory of misfolding and aggregation of pleiomorphic proteins associated with neurodegenerative diseases. In this model, fibrillization of tau is initiated by the coupled binding and folding of the MTB domains that yields antiparallel homodimers, in analogy to folding of split inteins. The free energy of binding is minimized when the antiparallel alignment brings about backbone-backbone H-bonding between the MTBD segments of similar “strand” propensities. To assess these propensities, a function of the NMR shielding tensors of the C α atoms is introduced as the folding potential function FP i ; the C α tensors are obtained by the quantum mechanical modeling of protein secondary structure (GIAO//B3LYP/D95 ** ). The calculated FP i plots show that the “strand” propensities of the MBTD segments, and hence the homodimer's register, can be affected by the relatively small changes in the environment's pH, as a result of protonation of MBTD's conserved histidines. The assembly of the antiparallel tau dimers into granular aggregates and their subsequent conversion into the parallel cross-β structure of paired helical filaments is expected to follow the same path as the previously described fibrillization of Aβ. Consequently, the core structure of the nascent tau fibril is determined by the register of the tau homodimer. This model accounts for the reported differences in (i) fibril-core structure of in vivo and in vitro filaments, (ii) cross-seeding of isoforms, (iii) effects of reducing/non-reducing conditions, (iv) effects of PHF6 mutations, and (v) homologs' aggregation properties. The proposed model also suggests that in contrast to Alzheimer's and chronic traumatic encephalopathy disease, the assembly of tau prions in Pick's disease would be facilitated by a moderate drop in pH that accompanies e.g., transit in the endosomal system, inflammation response or an ischemic injury.

show abstract

Section: Resultsmentioning

confidence: 99%

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

Cieplak

2019

Front. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Однако их результаты соответствуют максимальным значениям рН, полученным нами. Одной из возможных причин такого разброса значений уровня рН здоровой мозговой ткани, помимо особенностей настройки и отличия оборудования, может являться разный возрастной состав группы испытуемых, так как уровень рН мозговой ткани с годами меняется [19]. Наша группа добровольцев имела малое различие в возрасте и, возможно, поэтому значения рН были практически одинаковы у большинства испытуемых.…”

Section: Discussionunclassified

Phosphorus (P) magnetic resonance spectroscopy for evaluation of brain tissue metabolism and measuring non-invasive pH. A study involving 23 volunteers. Part I

Pronin¹,

Захарова²,

Podoprigora³

et al. 2019

Vopr. neirokhir.

View full text Add to dashboard Cite

Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model

et al. 2022

View full text Add to dashboard Cite

Background Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). Aim To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model. Methods LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brainECF) and intracellular (brainICF) fluids and cerebrospinal fluid of the subarachnoid space (CSFSAS) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer’s patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer’s based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC50 values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. Results The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. BrainECF, brainICF and CSFSAS PK profile relationships were different between the drugs. Aging and Alzheimer’s had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC50 values were not reached. Semagacestat brain PK plateau levels were below the IC50 of gamma-secretase for half of the interdose interval, unlike CSFSAS PK profiles that were consistently above IC50. Conclusion This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSFSAS PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer’s, this study shows that the impact of aging and Alzheimer’s pathology on CNS distribution of the five drugs is insignificant.

show abstract

Brain aging: Evaluation of pH using phosphorus magnetic resonance spectroscopy

Abstract: The present findings might provide a valuable basis for further research into "healthy aging" as well as pathology in older adults. Geriatr Gerontol Int 2018; 18: 881-885.

Cited by 4 publications

References 17 publications

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

Phosphorus (P) magnetic resonance spectroscopy for evaluation of brain tissue metabolism and measuring non-invasive pH. A study involving 23 volunteers. Part I

Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model

Contact Info

Product

Resources

About