P4-081: Diurnal fluctuation of amyloid-β in the brain interstitial fluid of young Tg2576 mice

El Sistema ◽

Arterial Pulsation ◽

Las vías de drenaje solutos del sistema nervioso central (SNC) participan en el recambio de liquido intersticial con el líquido cefalorraquídeo (LIT-LCR), generando un estado de homeostasis. Las alteraciones dentro de este sistema homeostático afectará la eliminación de solutos del espacio intersticial (EIT) como el péptido βa y proteína tau, los cuales son sustancias neurotóxicas para el SNC. Se han utilizado técnicas experimentales para poder analizar el intercambio LIT-LCR, las cuales revelan que este intercambio tiene una estructura bien organizada. La eliminación de solutos del SNC no tiene una estructura anatómica propiamente, se han descubierto vías de eliminación de solutos a través de marcadores florecentes en el espacio subaracnoideo, cisternas de la base y sistema ventricular que nos permiten observar una serie de vías ampliamente distribuidas en el cerebro. El LCR muestra que tiene una función linfática debido a su recambio con el LIT a lo largo de rutas paravasculares. Estos espacios que rodean la superficie arterial así como los espacios de Virchow-Robin y el pie astrocitico junto con la AQP-4, facilitan la entrada de LCR para-arterial y el aclaramiento de LIT para-venoso dentro del cerebro. El flujo y dirección que toma el LCR por estas estructuras, es conducido por la pulsación arterial. Esta función será la que finalmente llevara a la eliminación de estas sustancias neurotóxicas. En base a la dependencia de este flujo para la eliminación de sustancias se propone que el sistema sea llamado “ la Vía Glinfática”. La bibliografía así como las limitaciones que se encuentran en esta revisión están dadas por la metodología de búsqueda que ha sido realizada principalmente en PubMed utilizando los siguientes términos Mesh: Cerebral Arterial Pulsation, the brain via paravascular, drainage of amyloid-beta, bulk flow of brain interstitial fluid, radiolabeled polyethylene glycols and albumin, amyloid-β, the perivascular astroglial sheath, Brain Glymphatic Transport.

Role of the glymphatic system in ageing and diabetes mellitus impaired cognitive function

Stroke and Vascular Neurology ◽

10.1136/svn-2018-000203 ◽

2019 ◽

Vol 4 (2) ◽

pp. 90-92 ◽

Cited By ~ 6

Author(s):

Li Zhang ◽

Michael Chopp ◽

Quan Jiang ◽

Zhenggang Zhang

Keyword(s):

Diabetes Mellitus ◽

Cognitive Impairment ◽

Interstitial Fluid ◽

Amyloid Β ◽

Brain Parenchyma ◽

Glymphatic System ◽

Impaired Cognitive Function ◽

Increased Risk ◽

Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment.

Fast uncertainty quantification of tracer distribution in the brain interstitial fluid with multilevel and quasi Monte Carlo

International Journal for Numerical Methods in Biomedical Engineering ◽

10.1002/cnm.3412 ◽

2020 ◽

Author(s):

Matteo Croci ◽

Vegard Vinje ◽

Marie E. Rognes

Keyword(s):

Monte Carlo ◽

Uncertainty Quantification ◽

Interstitial Fluid ◽

Quasi Monte Carlo ◽

Tracer Distribution ◽

Effects of growth hormone–releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model

Brain Behavior and Immunity ◽

10.1016/j.bbi.2014.09.005 ◽

2015 ◽

Vol 47 ◽

pp. 163-171 ◽

Cited By ~ 7

Author(s):

Fan Liao ◽

Tony J. Zhang ◽

Thomas E. Mahan ◽

Hong Jiang ◽

David M. Holtzman

Keyword(s):

Growth Hormone ◽

Mouse Model ◽

Transgenic Mouse ◽

Interstitial Fluid ◽

Amyloid Β ◽

Transgenic Mouse Model ◽

Growth Hormone Releasing Hormone ◽

Releasing Hormone ◽

Brain Interstitial Fluid

In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis

Molecular Neurodegeneration ◽

10.1186/1750-1326-8-13 ◽

2013 ◽

Vol 8 (1) ◽

pp. 13 ◽

Cited By ~ 59

Author(s):

Jason D Ulrich ◽

Jack M Burchett ◽

Jessica L Restivo ◽

Dorothy R Schuler ◽

Philip B Verghese ◽

...

Keyword(s):

Apolipoprotein E ◽

Interstitial Fluid ◽

In Vivo Measurement ◽

Tau in the brain interstitial fluid is fragmented and seeding-competent

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.09.013 ◽

2021 ◽

Author(s):

Erica Barini ◽

Gudrun Plotzky ◽

Yulia Mordashova ◽

Jonas Hoppe ◽

Esther Rodriguez-Correa ◽

...

Keyword(s):

Interstitial Fluid ◽

In Vivo MR Imaging of the Flow of the Brain Interstitial Fluid

Neuroscience and Biomedical Engineering ◽

10.2174/2213385205666170127125448 ◽

2017 ◽

Vol 4 (4) ◽

pp. 225-229

Author(s):

Bin Liu ◽

Cunjing Zhang ◽

Yuliang Li

Keyword(s):

Mr Imaging ◽

Interstitial Fluid ◽

Tau in the brain interstitial fluid is fragmented and seeding-competent

10.1101/2020.07.15.205724 ◽

2020 ◽

Author(s):

Erica Barini ◽

Gudrun Plotzky ◽

Yulia Mordashova ◽

Jonas Hoppe ◽

Esther Rodriguez-Correa ◽

...

Keyword(s):

Transgenic Mice ◽

Interstitial Fluid ◽

List Type ◽

Fragmentation Pattern ◽

Tau Pathology ◽

Brain Areas ◽

Tau Aggregation ◽

SUMMARYIn Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells and notably, only a small fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that only a subset of Tau accounts for ISF seeding competence and have the potential to contribute to the propagation of Tau pathology.Graphical abstractHighlights✓In transgenic mice, interstitial fluid comprises several Tau fragments spanning the entire Tau sequence.✓Interstitial fluid Tau concentration decreases with Tauopathy progression, while phosphorylation increases.✓Only interstitial fluid from mice with established Tauopathy is seeding competent in vitro.✓Interstitial fluid seeding competence is driven by less soluble, aggregated and phosphorylated Tau species.In BriefBarini et al. show that in the brain interstitial fluid of Tau transgenic mice, truncated Tau decreases, while its phosphorylation increases during the progression of pathology. A subset of less soluble, aggregated and phosphorylated ISF Tau induces Tau aggregation in cells.

Determination of in vivo steady-state unbound drug concentration in the brain interstitial fluid by microdialysis

International Journal of Pharmaceutics ◽

10.1016/0378-5173(92)90006-n ◽

1992 ◽

Vol 81 (2-3) ◽

pp. 143-152 ◽

Cited By ~ 40

Author(s):

Terasaki Tetsuya ◽

Deguchi Yoshiharu ◽

Kasama Yuko ◽

William M. Pardridge ◽

Tsuji Akira

Keyword(s):

Steady State ◽

Drug Concentration ◽

Interstitial Fluid ◽

Dysregulated Gut Homeostasis Observed Prior to the Accumulation of the Brain Amyloid-β in Tg2576 Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21051711 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1711 ◽

Cited By ~ 6

Author(s):

Pedram Honarpisheh ◽

Caroline R. Reynolds ◽

Maria P. Blasco Conesa ◽

Jose F. Moruno Manchon ◽

Nagireddy Putluri ◽

...

Keyword(s):

Amyloid Β ◽

Tg2576 Mouse ◽

Intestinal Epithelial ◽

Gut Dysfunction ◽

Gut Homeostasis ◽

Plasma Cytokines ◽

Aβ Aggregation ◽

The Brain ◽

Tg2576 Mice ◽

Junction Proteins

Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.