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1.
Nat Neurosci ; 25(5): 567-576, 2022 05.
Article in English | MEDLINE | ID: mdl-35501382

ABSTRACT

Interactions between the immune and central nervous systems strongly influence brain health. Although the blood-brain barrier restricts this crosstalk, we now know that meningeal gateways through brain border tissues facilitate intersystem communication. Cerebrospinal fluid (CSF), which interfaces with the glymphatic system and thereby drains the brain's interstitial and perivascular spaces, facilitates outward signaling beyond the blood-brain barrier. In the present study, we report that CSF can exit into the skull bone marrow. Fluorescent tracers injected into the cisterna magna of mice migrate along perivascular spaces of dural blood vessels and then travel through hundreds of sub-millimeter skull channels into the calvarial marrow. During meningitis, bacteria hijack this route to invade the skull's hematopoietic niches and initiate cranial hematopoiesis ahead of remote tibial sites. As skull channels also directly provide leukocytes to meninges, the privileged sampling of brain-derived danger signals in CSF by regional marrow may have broad implications for inflammatory neurological disorders.


Subject(s)
Glymphatic System , Meningitis, Bacterial , Animals , Bone Marrow , Brain/blood supply , Cerebrospinal Fluid , Glymphatic System/physiology , Hematopoiesis , Mice , Skull
2.
J Cereb Blood Flow Metab ; 41(7): 1501-1516, 2021 07.
Article in English | MEDLINE | ID: mdl-33444096

ABSTRACT

Reductions of baseline cerebral blood flow (CBF) of ∼10-20% are a common symptom of Alzheimer's disease (AD) that appear early in disease progression and correlate with the severity of cognitive impairment. These CBF deficits are replicated in mouse models of AD and recent work shows that increasing baseline CBF can rapidly improve the performance of AD mice on short term memory tasks. Despite the potential role these data suggest for CBF reductions in causing cognitive symptoms and contributing to brain pathology in AD, there remains a poor understanding of the molecular and cellular mechanisms causing them. This review compiles data on CBF reductions and on the correlation of AD-related CBF deficits with disease comorbidities (e.g. cardiovascular and genetic risk factors) and outcomes (e.g. cognitive performance and brain pathology) from studies in both patients and mouse models, and discusses several potential mechanisms proposed to contribute to CBF reductions, based primarily on work in AD mouse models. Future research aimed at improving our understanding of the importance of and interplay between different mechanisms for CBF reduction, as well as at determining the role these mechanisms play in AD patients could guide the development of future therapies that target CBF reductions in AD.


Subject(s)
Alzheimer Disease/pathology , Cerebrovascular Circulation , Cerebrovascular Disorders/complications , Alzheimer Disease/etiology , Animals , Disease Models, Animal , Humans
3.
Sci Rep ; 10(1): 9884, 2020 06 18.
Article in English | MEDLINE | ID: mdl-32555372

ABSTRACT

Obesity is linked to increased risk for and severity of Alzheimer's disease (AD). Cerebral blood flow (CBF) reductions are an early feature of AD and are also linked to obesity. We recently showed that non-flowing capillaries, caused by adhered neutrophils, contribute to CBF reduction in mouse models of AD. Because obesity could exacerbate the vascular inflammation likely underlying this neutrophil adhesion, we tested links between obesity and AD by feeding APP/PS1 mice a high fat diet (Hfd) and evaluating behavioral, physiological, and pathological changes. We found trends toward poorer memory performance in APP/PS1 mice fed a Hfd, impaired social interactions with either APP/PS1 genotype or a Hfd, and synergistic impairment of sensory-motor function in APP/PS1 mice fed a Hfd. The Hfd led to increases in amyloid-beta monomers and plaques in APP/PS1 mice, as well as increased brain inflammation. These results agree with previous reports showing obesity exacerbates AD-related pathology and symptoms in mice. We used a crowd-sourced, citizen science approach to analyze imaging data to determine the impact of the APP/PS1 genotype and a Hfd on capillary stalling and CBF. Surprisingly, we did not see an increase in the number of non-flowing capillaries or a worsening of the CBF deficit in APP/PS1 mice fed a Hfd as compared to controls, suggesting that capillary stalling is not a mechanistic link between a Hfd and increased severity of AD in mice. Reducing capillary stalling by blocking neutrophil adhesion improved CBF and short-term memory function in APP/PS1 mice, even when fed a Hfd.


Subject(s)
Alzheimer Disease/pathology , Cerebrovascular Circulation/physiology , Diet, High-Fat , Neurons/pathology , Amyloid beta-Protein Precursor/genetics , Animals , Behavior, Animal , Blood Vessels/diagnostic imaging , Blood Vessels/physiology , Cytokines/metabolism , Disease Models, Animal , Female , Genotype , Male , Memory, Short-Term , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/metabolism , Presenilin-1/genetics
4.
Nat Neurosci ; 22(3): 413-420, 2019 03.
Article in English | MEDLINE | ID: mdl-30742116

ABSTRACT

Cerebral blood flow (CBF) reductions in Alzheimer's disease patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences for Alzheimer's disease pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to in wild-type animals, largely due to neutrophils that had adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to both an immediate increase in CBF and rapidly improved performance in spatial and working memory tasks. This study identified a previously uncharacterized cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of Alzheimer's disease and demonstrated that improving CBF rapidly enhanced short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a strategy for improving cognition in Alzheimer's disease patients.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/psychology , Brain/blood supply , Brain/metabolism , Memory/physiology , Neutrophils/metabolism , Amyloid beta-Peptides/metabolism , Animals , Antibodies/administration & dosage , Antigens, Ly/administration & dosage , Antigens, Ly/immunology , Brain/physiopathology , Capillaries/physiopathology , Disease Models, Animal , Female , Male , Memory/drug effects , Mice, Inbred C57BL , Mice, Transgenic , Models, Neurological , Neutrophils/immunology , Peptide Fragments/metabolism
5.
Nat Methods ; 14(4): 388-390, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28218900

ABSTRACT

High-resolution optical imaging is critical to understanding brain function. We demonstrate that three-photon microscopy at 1,300-nm excitation enables functional imaging of GCaMP6s-labeled neurons beyond the depth limit of two-photon microscopy. We record spontaneous activity from up to 150 neurons in the hippocampal stratum pyramidale at ∼1-mm depth within an intact mouse brain. Our method creates opportunities for noninvasive recording of neuronal activity with high spatial and temporal resolution deep within scattering brain tissues.


Subject(s)
Brain/cytology , Microscopy, Fluorescence, Multiphoton/methods , Neurons/physiology , Animals , Brain/physiology , Calmodulin/analysis , Calmodulin/metabolism , Green Fluorescent Proteins/analysis , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hippocampus/cytology , Hippocampus/physiology , Male , Mice, Inbred C57BL , Mice, Transgenic , Recombinant Fusion Proteins/analysis , Recombinant Fusion Proteins/metabolism , Recombinant Proteins/analysis , Recombinant Proteins/genetics , Recombinant Proteins/metabolism
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