Toward three-dimensional models to study neurovascular unit functions in health and disease.

The high metabolic demands of the brain require an efficient vascular system to be coupled with neural activity to supply adequate nutrients and oxygen. This supply is coordinated by the action of neurons, glial and vascular cells, known collectively as the neurovascular unit, which temporally and spatially regulate local cerebral blood flow through a process known as neurovascular coupling. In many neurodegenerative diseases, changes in functions of the neurovascular unit not only impair neurovascular coupling but also permeability of the blood-brain barrier, cerebral blood flow and clearance of waste from the brain.

Development of a novel, sensitive translational immunoassay to detect plasma glial fibrillary acidic protein (GFAP) after murine traumatic brain injury.

Background: Glial fibrillary acidic protein (GFAP) has emerged as a promising fluid biomarker for several neurological indications including traumatic brain injury (TBI), a leading cause of death and disability worldwide. In humans, serum or plasma GFAP levels can predict brain abnormalities including hemorrhage on computed tomography (CT) scans and magnetic resonance imaging (MRI). However, assays to quantify plasma or serum GFAP in preclinical models are not yet available.

An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative diseases.

Introduction: The neurovascular unit (NVU) - the interaction between the neurons and the cerebrovasculature - is increasingly important to interrogate through human-based experimental models. Although advanced models of cerebral capillaries have been developed in the last decade, there is currently no in vitro 3-dimensional (3D) perfusible model of the human cortical arterial NVU.

Method: We used a tissue-engineering technique to develop a scaffold-directed, perfusible, 3D human NVU that is cultured in native-like flow conditions that mimics the anatomy and physiology of cortical penetrating arteries.

Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E.

Background: Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer's disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood.

Methods: Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding.

Results: We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation.

Increased severity of the CHIMERA model induces acute vascular injury, sub-acute deficits in memory recall, and chronic white matter gliosis.

Traumatic brain injury (TBI) is a leading cause of death and disability in modern societies. Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head and contribute to disability throughout the injury severity spectrum. CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter gliosis and axonal damage.

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice.

Background: Alzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD.

HDL from an Alzheimer's disease perspective.

Purpose Of Review: We review current knowledge regarding HDL and Alzheimer's disease, focusing on HDL's vasoprotective functions and potential as a biomarker and therapeutic target for the vascular contributions of Alzheimer's disease.

Recent Findings: Many epidemiological studies have observed that circulating HDL levels associate with decreased Alzheimer's disease risk. However, it is now understood that the functions of HDL may be more informative than levels of HDL cholesterol (HDL-C).

Vasoprotective Functions of High-Density Lipoproteins Relevant to Alzheimer's Disease Are Partially Conserved in Apolipoprotein B-Depleted Plasma.

High-density lipoproteins (HDL) are known to have vasoprotective functions in peripheral arteries and many of these functions extend to brain-derived endothelial cells. Importantly, several novel brain-relevant HDL functions have been discovered using brain endothelial cells and in 3D bioengineered human arteries. The cerebrovascular benefits of HDL in healthy humans may partly explain epidemiological evidence suggesting a protective association of circulating HDL levels against Alzheimer's Disease (AD) risk.

CHIMERA repetitive mild traumatic brain injury induces chronic behavioural and neuropathological phenotypes in wild-type and APP/PS1 mice.

Background: The annual incidence of traumatic brain injury (TBI) in the United States is over 2.5 million, with approximately 3-5 million people living with chronic sequelae. Compared with moderate-severe TBI, the long-term effects of mild TBI (mTBI) are less understood but important to address, particularly for contact sport athletes and military personnel who have high mTBI exposure.

Age at injury and genotype modify acute inflammatory and neurofilament-light responses to mild CHIMERA traumatic brain injury in wild-type and APP/PS1 mice.

Peak incidence of traumatic brain injury (TBI) occurs in both young and old individuals, and older age at injury is associated with worse outcome and poorer recovery. Moderate-severe TBI is a reported risk factor for dementia, including Alzheimer's disease (AD), but whether mild TBI (mTBI) alters AD pathogenesis is not clear. To delineate how age at injury and predisposition to amyloid formation affect the acute response to mTBI, we used the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of TBI to induce two mild injuries in wild-type (WT) and APP/PS1 mice at either 6 or 13months of age and assessed behavioural, histological and biochemical changes up to 14days post-injury.

Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels.

Amyloid plaques, consisting of deposited beta-amyloid (Aβ), are a neuropathological hallmark of Alzheimer's Disease (AD). Cerebral vessels play a major role in AD, as Aβ is cleared from the brain by pathways involving the cerebrovasculature, most AD patients have cerebrovascular amyloid (cerebral amyloid angiopathy (CAA), and cardiovascular risk factors increase dementia risk. Here we present a notable advance in vascular tissue engineering by generating the first functional 3-dimensioinal model of CAA in bioengineered human vessels.

High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture.

Background: Alzheimer's Disease (AD), characterized by accumulation of beta-amyloid (Aβ) plaques in the brain, can be caused by age-related failures to clear Aβ from the brain through pathways that involve the cerebrovasculature. Vascular risk factors are known to increase AD risk, but less is known about potential protective factors. We hypothesize that high-density lipoproteins (HDL) may protect against AD, as HDL have vasoprotective properties that are well described for peripheral vessels.

Fasting upregulates adipose triglyceride lipase and hormone-sensitive lipase levels and phosphorylation in mouse kidney.

Circulating non-esterified fatty acids (NEFA) rise during fasting and are taken up by the kidneys, either directly from the plasma or during re-uptake of albumin from glomerular filtrate, and are stored as triacylglycerol (TAG). Subsequent utilization of stored fatty acids requires their hydrolytic release from cellular lipid droplets, but relatively little is known about renal lipolysis. We found that total [(3)H]triolein hydrolase activity of kidney lysates was significantly increased by 15% in the fasted state.

Microglial cell activation increases saturated and decreases monounsaturated fatty acid content, but both lipid species are proinflammatory.

Neuroinflammation is a component of age-related neurodegenerative diseases and cognitive decline. Saturated (SFA) and monounsaturated (MUFA) fatty acids are bioactive molecules that may play different extrinsic and intrinsic roles in neuroinflammation, serving as exogenous ligands for cellular receptors, or endogenous components of cell structural, energetic and signaling pathways. We determined the fatty acyl profile of BV2 microglial cells before and after acute activation with lipopolysaccharide (LPS).