Multisensory gamma stimulation promotes glymphatic clearance of amyloid
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE249644 | GEO | 2023/12/23
REPOSITORIES: GEO
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2015-11-05 | E-GEOD-74669 | biostudies-arrayexpress
Project description:Das2010 - Effect of a gamma-secretase
inhibitor on Amyloid-beta dynamics
This model is described in the article:
Modeling effect of a
?-secretase inhibitor on amyloid-? dynamics reveals significant
role of an amyloid clearance mechanism.
Das R, Nachbar RB, Edelstein-Keshet
L, Saltzman JS, Wiener MC, Bagchi A, Bailey J, Coombs D, Simon
AJ, Hargreaves RJ, Cook JJ.
Bull. Math. Biol. 2011 Jan; 73(1):
230-247
Abstract:
Aggregation of the small peptide amyloid beta (A?) into
oligomers and fibrils in the brain is believed to be a
precursor to Alzheimer's disease. A? is produced via multiple
proteolytic cleavages of amyloid precursor protein (APP),
mediated by the enzymes ?- and ?-secretase. In this study, we
examine the temporal dynamics of soluble (unaggregated) A? in
the plasma and cerebral-spinal fluid (CSF) of rhesus monkeys
treated with different oral doses of a ?-secretase inhibitor. A
dose-dependent reduction of A? concentration was observed
within hours of drug ingestion, for all doses tested. A?
concentration in the CSF returned to its predrug level over the
monitoring period. In contrast, A? concentration in the plasma
exhibited an unexpected overshoot to as high as 200% of the
predrug concentration, and this overshoot persisted as late as
72 hours post-drug ingestion. To account for these
observations, we proposed and analyzed a minimal physiological
model for A? dynamics that could fit the data. Our analysis
suggests that the overshoot arises from the attenuation of an
A? clearance mechanism, possibly due to the inhibitor. Our
model predicts that the efficacy of A? clearance recovers to
its basal (pretreatment) value with a characteristic time of
>48 hours, matching the time-scale of the overshoot. These
results point to the need for a more detailed investigation of
soluble A? clearance mechanisms and their interaction with
A?-reducing drugs.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000551.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2014-09-23 | BIOMD0000000551 | BioModels
Project description:Qosa2014 - Mechanistic modeling that
describes Aβ clearance across BBB
Qosa2014 - Mechanistic modeling that
describes Aβ clearance across BBB.
Encoded non-curated model. Issues:
- Confusing equation 6
- Missing initial values for spices
This model is described in the article:
Differences in amyloid-?
clearance across mouse and human blood-brain barrier models:
kinetic analysis and mechanistic modeling.
Qosa H, Abuasal BS, Romero IA,
Weksler B, Couraud PO, Keller JN, Kaddoumi A.
Neuropharmacology 2014 Apr; 79:
668-678
Abstract:
Alzheimer's disease (AD) has a characteristic hallmark of
amyloid-? (A?) accumulation in the brain. This accumulation of
A? has been related to its faulty cerebral clearance. Indeed,
preclinical studies that used mice to investigate A? clearance
showed that efflux across blood-brain barrier (BBB) and brain
degradation mediate efficient A? clearance. However, the
contribution of each process to A? clearance remains unclear.
Moreover, it is still uncertain how species differences between
mouse and human could affect A? clearance. Here, a modified
form of the brain efflux index method was used to estimate the
contribution of BBB and brain degradation to A? clearance from
the brain of wild type mice. We estimated that 62% of
intracerebrally injected (125)I-A?40 is cleared across BBB
while 38% is cleared by brain degradation. Furthermore,
in vitro and in silico studies were performed to compare
A? clearance between mouse and human BBB models. Kinetic
studies for A?40 disposition in bEnd3 and hCMEC/D3 cells,
representative in vitro mouse and human BBB models,
respectively, demonstrated 30-fold higher rate of (125)I-A?40
uptake and 15-fold higher rate of degradation by bEnd3 compared
to hCMEC/D3 cells. Expression studies showed both cells to
express different levels of P-glycoprotein and RAGE, while LRP1
levels were comparable. Finally, we established a mechanistic
model, which could successfully predict cellular levels of
(125)I-A?40 and the rate of each process. Established
mechanistic model suggested significantly higher rates of A?
uptake and degradation in bEnd3 cells as rationale for the
observed differences in (125)I-A?40 disposition between mouse
and human BBB models. In conclusion, current study demonstrates
the important role of BBB in the clearance of A? from the
brain. Moreover, it provides insight into the differences
between mouse and human BBB with regards to A? clearance and
offer, for the first time, a mathematical model that describes
A? clearance across BBB.
This model is hosted on
BioModels Database
and identified by:
MODEL1409240002.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
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