Blood–brain barrier (BBB) pathways to neurodegeneration in dementia and Alzheimer’s disease (AD)
- A: In the normal capillary, there is an intact BBB composed of tightly joined endothelial cells and supported by mural pericytes, as shown in this simplified schematic. The BBB normally selectively regulates the passage of molecules from blood to brain and vice versa, and restricts entry of blood-derived products and toxins into the brain. There are many transporters and receptors along the BBB that permit molecules to cross the BBB via substrate-specific transport systems, some of which are particularly relevant to AD pathophysiogenesis, as illustrated in the graphics above. For example, the normal BBB has high expression of the glucose transporter (GLUT1),moderate expression of low-density lipoprotein receptor-related protein-1 (LRP1), and minimal expression of receptor for advanced glycation end-products (RAGE).
- B: In the AD capillary, there is a vicious cascade of events that can lead to neurodegeneration, as shown in this schematic and described as follows. 1. Pericytes degenerate and detach. 2. The BBB becomes leaky. 3. Blood-derived molecules like fibrinogen, thrombin, and plasminogen leak from vessels and are directly toxic to neurons and can further induce BBB damage. Erythrocyte extravasation induces accumulation of hemoglobin-derived iron which causes generation of reactive oxygen species (ROS) and oxidative stress to neurons, and albumin promotes local tissue edema. 4. BBB transporter expression is altered, e.g., LRP1 and GLUT1 expressions are significantly reduced, whereas RAGE expression is increased.
The alterations in LRP1 and RAGE (transportS Aβ from the blood into the brain ) reduce the clearance and increase the uptake of Aβ into the brain, respectively, leading to Aβ accumulation in the brain. Also, normal cerebrovascular functions are disrupted by vascular pathologies including 5. Cerebral amyloid angiopathy (CAA), 6. Damaged and thickening of the basement membrane, and 7. String vessels.
Patients with hereditary Dutch, Iowa, Arctic, Flemish, Italian, or Piedmont L34V vasculotropic mutations develop CAA followed by rupture of blood vessels and hemorrhagic strokes in midlife. CAA is known to worsen AD pathology and occurs in 80% of AD patients. CAA likely develops as a result of the ineffective transvascular and perivascular clearance of Aβ, as well as poor Aβ clearance by arterial VSMCs. It was recently reported that microvascular rather than arenchymal Aβ deposits are associated with early behavioral deficits in AD transgenic mice. Individuals with CAA carrying APOE4 allele(s) have accelerated vascular pathology that can modulate Aβ accumulation.
Reduced glucose utilization
Cognitively normal individuals with genetic risk for AD or positive AD family history and mild or no cognitive impairment that later develop AD all have reduced glucose utilization in the hippocampus, parietotemporal cortex, and/or posterior cingulate cortex measured by 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-PET, which occurs prior to brain atrophy and neuronal dysfunction. Brain glucose uptake correlateswith the level of GLUT1 on cerebralmicrovessels.
Other contributing factors: Diabetes, hypertension, pollution/nanoparticles
Air pollution has been shown to increase the risk of AD and AD-like brain pathologies. Young residents of the Mexico City Metropolitan Area (MCMA) exposed to air pollution display cognitive impairment, BBB disruption, Aβ42 plaques, and hyperphosphorylated tau accumulation,which are exacerbated in APOE4 carriers. Children from the MCMA have increased serum autoantibodies against neuronal proteins, likely due to compromised brain immunity and BBB breakdown. In mouse experimental studies, aerosolized nickel nanoparticles caused a rapid and drastic increase in Aβ40 and Aβ42. Also, APOE null mice exposed to mixed vehicle exhaust have accelerated BBB breakdown, decreased expression of tight junction proteins (e.g., occludin, claudin-5) and increased generation of reactive oxygen species activity.
Many types of nanomaterials are emerging in medical science and research for their potential as biosensors, biomaterials, tissue engineering, DNA modification, or drug delivery. The sources of nanoparticles that humans are exposed to are numerous and include nanoscaled debris from hip replacements, prostheses, cosmetics, sunscreen, and many others. Unfortunately, nanoparticles have proven to be toxic in a number of host systems. Highly active nanoparticles (e.g., silica coated to be hydrophilic, hydrophobic, or amphiphilic) can be taken up by cellular membranes, including the BBB, and cross the membrane passively or by carrier-mediated endocytosis.
Experimental studies in rodents have shown that silver, copper, or aluminum/aluminum oxide nanoparticles disrupt the BBB, reduce the expression of endothelial tight junctions, decrease CBF, and induce edema, synaptic
dysfunction, and neurodegeneration. Interestingly, silver and copper nanoparticle exposure exacerbated BBB dysfunction when accompanying sleep deprivation or diabetes.
Peripheral inflammation is being considered a possible risk factor for AD and dementia. Infectious agents including pneumonia, B. burgdorferi, Helicobacter pylori, and herpes simplex virus 1 (HSV-1) have been identified in AD post-mortembrain tissue. Interestingly,
HSV-1 infections are foundmore often in APOE4 carriers,which have increased BBB permeability. Additionally, dementia patients have a two-fold increased mortality rate from pneumonia, and pneumonia patients have elevated MMP-9 levels in their serum, which is known to be linked to BBB breakdown.
Poor oral hygiene, oral inflammation, and tooth loss worsen with age and are risk factors for AD. Recently, fungus was identified in post-mortem brain tissue from AD subjects and was found to localize around blood vessels in AD brain tissue. In AD, infectious agents likely enter the brain through a leaky, disrupted BBB and cause more detrimental effects than they would normally if the BBB were
Diet and AD
Recent studies report that diet can mediate the vasculoplastic reserve of the hippocampus. For example, consuming high levels of cocoa flavanols increased capillary density and enhanced dentate gyrus-associated cognitive function in cognitively normal healthy subjects
This suggests an interaction between vasculoplasticity and neuronal plasticity during normal aging and dementia, but how this relationship is affected by lifestyle and vascular risk factors is currently unclear and should be investigated in future studies.
Growing evidence supports the benefits of a Mediterranean diet in protecting against dementia and prolonging one’s cognitive reserve during aging. Age-related cognitive decline was attenuated in individuals consuming a Mediterranean diet, as found in a recent study of the Mediterranean-Dietary Approach to Systolic Hypertension (DASH) diet intervention for neurodegenerative delay (MIND).
In comparing Mediterranean and Western diets, the primary difference is the source and proportion of dietary fats, with olive oil specifically being the main fat consumed in the Mediterranean diet and high levels of saturated fatty acids and simple carbohydrates being consumed in Western diets. Microvascular dysfunction is evident in rodent models fed unhealthy diets, namely, those fed diets of Western culture, high fat, and high cholesterol.
An intact BBB is needed for proper cholesterol metabolism. In CSF, decreased cholesterol levels correlate with decreased Aβ42 and increased CSF APPα and APPβ (products of APP processing) levels, supporting an association between disrupted cholesterol metabolism and increased amyloidogenesis.
Resveratrol is a biologically active plant-derived phytoalexin. Resveratrol has been shown to cross BBB and regulate expression of MMPs, reduce pericyte loss, maintain integrity of BBB, and promote Aβ clearance [224–226]. Treatment with resveratrol completely reversed diabetes-induced vascular dysfunction by reducing capillary leakage, pericyte degeneration, and VEGF protein expression in the murine retina.
An earlier study has shown that resveratrol inhibits RAGE expression in vascular cells,which is implicated in Aβ transport into the brain and accelerated Aβ pathology in a mousemodel.
Furthermore, long-term consumption of resveratrol reduced oxidative stress and prevented behavioral deficits in a rat model with disrupted NVU.
Olive oil is high in essential omega-3 fatty acids, the major component of which is docosahexaenoic acid (DHA), and has long been reported to benefit cognition and overall brain health. DHA cannot be synthesized by the body and thus must be consumed, and the primary transporter of DHA from blood-to-brain is the major facilitator superfamily domain containing 2A (MFSD2A) at the BBB.
Individuals with AD have lower CSF DHA lipid levels, and those with mild dementia have lower CSF α-liolenic acid levels. Interestingly, reduced MFSD2A expression at the BBB can lead to a loss of its important functions, including maintenance of BBB integrity and omega-3 fatty acid transport into the brain.
Transgenic APOE4 mice also exhibit reduced uptake of DHA into the brain compared with transgenic APOE2 mice. But, whether this is related to reduced Mfsd2a expression is currently unknown. Additional studies are needed elucidate the underlying mechanisms of MFSD2A and fatty acids in relation to dementia and AD.
Exercise and environmental enrichment
Regular exercise and physical activity, particularly during midlife, are associated with improved cerebrovascular function and reduced rates of dementia and AD. Individuals that exercised regularly for 28 days exhibited reduced plasma homocysteine levels and increased endothelial progenitor cells in peripheral blood, factors that protect against vascular damage and cognitive impairment.
Experimental studies in diabetic rats have shown that treadmill exercise maintains claudin-5 expression at the BBB compared to rats not receiving exercise. Mechanistically, physical activity and cognitive stimulation in the form of enriched environment (e.g., tunnels, balls, ladders, and running wheel) accelerated Aβ enzymatic degradation and enhanced transvascular Aβ clearance, reducing Aβ accumulation in brains of AD transgenic mouse models.
Physical activity promoted Aβ clearance frombrain to blood via upregulation of LRP1 and downregulation of RAGE at the BBB. Mice without access to a running wheel had decreased occludin tight junction levels and disrupted BBB integrity. Although recent attention has been given to exercise, additional studies are needed to more completely understand the mechanism underlying its beneficial effects.
Source: Nelson et al, Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease, Department of Physiology and Biophysics and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA
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