Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Brain ; 147(6): 2214-2229, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38802114

ABSTRACT

Mild traumatic brain injury (mTBI) has emerged as a potential risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy. Blast mTBI, caused by exposure to a pressure wave from an explosion, is predominantly experienced by military personnel and has increased in prevalence and severity in recent decades. Yet the underlying pathology of blast mTBI is largely unknown. We examined the expression and localization of AQP4 in human post-mortem frontal cortex and observed distinct laminar differences in AQP4 expression following blast exposure. We also observed similar laminar changes in AQP4 expression and localization and delayed impairment of glymphatic function that emerged 28 days following blast injury in a mouse model of repetitive blast mTBI. In a cohort of veterans with blast mTBI, we observed that blast exposure was associated with an increased burden of frontal cortical MRI-visible perivascular spaces, a putative neuroimaging marker of glymphatic perivascular dysfunction. These findings suggest that changes in AQP4 and delayed glymphatic impairment following blast injury may render the post-traumatic brain vulnerable to post-concussive symptoms and chronic neurodegeneration.


Subject(s)
Aquaporin 4 , Blast Injuries , Glymphatic System , Adult , Aged , Animals , Female , Humans , Male , Mice , Middle Aged , Aquaporin 4/metabolism , Blast Injuries/complications , Blast Injuries/pathology , Blast Injuries/metabolism , Brain Concussion/metabolism , Brain Concussion/complications , Brain Concussion/pathology , Brain Concussion/physiopathology , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/pathology , Frontal Lobe/metabolism , Frontal Lobe/pathology , Frontal Lobe/diagnostic imaging , Glymphatic System/metabolism , Glymphatic System/pathology , Magnetic Resonance Imaging , Mice, Inbred C57BL , Veterans
2.
Alzheimers Res Ther ; 14(1): 59, 2022 04 26.
Article in English | MEDLINE | ID: mdl-35473943

ABSTRACT

BACKGROUND: Slowed clearance of amyloid ß (Aß) is believed to underlie the development of Aß plaques that characterize Alzheimer's disease (AD). Aß is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aß clearance, and promotes Aß plaque formation. METHODS: To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the α-syntrophin (Snta1) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid ß levels. RESULTS: In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing Aß and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid ß levels. CONCLUSIONS: These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations.


Subject(s)
Alzheimer Disease , Aquaporin 4/metabolism , Glymphatic System , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Aquaporin 4/genetics , Glymphatic System/metabolism , Glymphatic System/pathology , Humans , Mice , Plaque, Amyloid/pathology
3.
J Cereb Blood Flow Metab ; 41(8): 1873-1885, 2021 08.
Article in English | MEDLINE | ID: mdl-33853406

ABSTRACT

Local blood flow in the brain is tightly coupled to metabolic demands, a phenomenon termed functional hyperemia. Both capillaries and arterioles contribute to the hyperemic response to neuronal activity via different mechanisms and timescales. The nature and specific signaling involved in the hyperemic response of capillaries versus arterioles, and their temporal relationship are not fully defined. We determined the time-dependent changes in capillary flux and diameter versus arteriolar velocity and flow following whisker stimulation using optical microangiography (OMAG) and two-photon microscopy. We further characterized depth-resolved responses of individual capillaries versus capillary networks. We hypothesized that capillaries respond first to neuronal activation, and that they exhibit a coordinated response mediated via endothelial-derived epoxyeicosatrienoates (EETs) acting on pericytes. To visualize peri-capillary pericytes, we used Tie2-GFP/NG2-DsRed mice, and to determine the role of endothelial-derived EETs, we compared cerebrovascular responses to whisker stimulation between wild-type mice and mice with lower endothelial EETs (Tie2-hsEH). We found that capillaries respond immediately to neuronal activation in an orchestrated network-level manner, a response attenuated in Tie2-hsEH and inhibited by blocking EETs action on pericytes. These results demonstrate that capillaries are first responders during functional hyperemia, and that they exhibit a network-level response mediated via endothelial-derived EETs' action on peri-capillary pericytes.


Subject(s)
Capillaries/physiology , Endothelium/metabolism , Neurons/physiology , Pericytes/metabolism , Regional Blood Flow/physiology , 8,11,14-Eicosatrienoic Acid/analogs & derivatives , 8,11,14-Eicosatrienoic Acid/pharmacology , Animals , Arterioles/physiology , Capillaries/drug effects , Electric Stimulation , Epoxide Hydrolases/metabolism , Hyperemia/physiopathology , Male , Mice , Mice, Inbred C57BL , Microscopy, Fluorescence, Multiphoton , Tomography, Optical Coherence , Vasoconstriction/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL
...