Table 1.

The effects of Alzheimer’s disease (AD) environmental risk factors and beneficial agents on blood-brain barrier (BBB) function

AD risk factor	Effects on BBB
Aging	Aging leads to barrier dysfunction and vascular hyperpermeability in peripheral and BBB [165]
Air pollution	Long-term air pollution disrupts the BBB in children and young adults and causes neuroinflammation, an altered brain innate immune response, and accumulation of Aβ and alpha-synuclein starting in childhood [213]
Alcohol abuse	Alcohol(ism) has deleterious effects on the BBB [284, 285]
Aluminum	Aluminum increases BBB permeability in rats [286]
Aβ	Aβ disrupts BBB integrity in mice [187]
Brain trauma (concussion)	Mild traumatic brain injury produces early disruption of the BBB in animal models and in human [287, 288].
Cerebral hypoperfusion/ischemia (Caused by carotid/leptomeningeal/circle of Willis atherosclerosis or by hypotension)	Cerebral hypoperfusion reduces oxygen, glucose, and other nutrient supply to the brain, damaging parenchymal cells and the BBB [289].
Copper/aluminum	Nanoparticles from aluminum, silver, or copper increase spinal cord pathology after trauma, an effect correlated with breakdown of the blood-spinal cord barrier [290]
Diabetes mellitus	BBB dysfunction plays a role in diabetes-associated neurological complications (stroke, vascular dementia, and cognitive deficits) [291]
High intake of sugary drinks associated with preclinical markers of AD (memory and MRI measures) [292]	Hyperglycemia impairs the integrity of the BBB [293].
Homocysteine	Hyperhomocysteinemia increases permeability of the BBB via N-methyl-D-aspartate (NMDA) receptor activation [294]
Hypercholesterolemia	High cholesterol disrupts the BBB, an effect blocked by simvastatin [295]
Hypertension	Hypertension causes BBB breakdown via mechanisms involving inflammation, oxidative stress, and vasoactive circulating molecules [296]
Obesity	Obesity induces systemic inflammation and BBB disruption in mice, an effect augmented by age [297]
Pesticides	Several pesticides are able to disrupt the BBB in animal models [298– 300]
Physical inactivity	Exercise in animal models of cerebral ischemia/stroke, diabetes, and brain metastasis has been shown to improve BBB function [301]. Physical activity counters the negative influence of PICALM, BIN1, and CLU risk alleles on episodic memory functioning in a dementia-free population [302] (all of these are expressed in the BBB proteome dataset) [303– 305]
Poor sleep	Sleep disruption or sleep apnea are both associated with impaired BBB function[306, 307]
Smoking	Nicotine and smoking disrupt brain microvasculature and the BBB [308]
Viruses capable of disrupting the BBB	Viruses infecting humans known to cause disruption of the BBB or endothelial junctions include HIV-1, human T-cell leukemia virus, lymphocytic choriomeningitis virus, and the West Nile virus [309]. Bacterial LPS is disruptive in BBB models [310]
Beneficial effects
Anti-inflammatories (NSAIDS) and H2 histamine receptor antagonism	Aspirin and celecoxib prevent disruption of the BBB in vesicular stomatitis virus-infected mice [311]. Dexamethasone and methylprednisolone as well as NSAIDs (ibuprofen and indomethacin) reduce vascular permeability in a rat glioma model [312]. Nimesulide (a selective cyclooxygenase-2 inhibitor) attenuates BBB disruption in animal models of cerebral ischemia [313]: Histamine causes BBB opening via H2 receptors and H2 receptor antagonism attenuates increased BBB permeability caused by hyperthermia in rats [314, 315]
Caffeine	Caffeine is effective against BBB disruption in animal models of AD or Parkinson’s disease [316]
Chocolate (caffeine, theobromine, and resveratrol)	Theobromine is a phosphodiesterase inhibitor and downregulates PDE4 in a glioma cell line [317]. PDE4 inhibition (rolipram) reduces BBB damage in ischemic stroke in mice [318]. Caffeine and theobromine are adenosine receptor antagonists [319]. Extracellular adenosine increases BBB permeability and adenosine receptor antagonism blocks the entry of inflammatory cells and soluble factors into the brain [320]
Folic acid	Vitamin B12-B6-folate treatment improves BBB function in patients with hyperhomocysteinemia and mild cognitive impairment [321]. Folic acid decreases BBB leakage and reactive astrogliosis following seizures in pregnant and prepubertal rats [322]
Melatonin	Melatonin protects BBB integrity by downregulating matrix metalloprotease activity (MMP9) [323]
Memantine	Memantine (approved for use in dementia patients) [242] blocks the deleterious effects of homocysteine on the BBB [294]
Estrogen	Estrogen protects against BBB breakdown in animal models of stroke or following LPS challenge and maintains barrier integrity [324– 327]
Components of the Mediterranean diet	Omega-3 fatty acids reduce BBB disruption in hypoxic/ischemic brain injury [328]. Fish oil reduces BBB disruption in a rat model of juvenile traumatic brain injury [329]. Virgin olive oil reduces BBB permeability following middle cerebral artery occlusion in rats [330]. Aged garlic extract protects against BBB disruption caused by a high saturated fatty acid diet in mice [331]. Resveratrol, a component of grape and red fruit skins, and red wine [332], maintains the integrity of the BBB after cerebral ischemia reperfusion in rats [333]
Statins	Statins have been reported to ameliorate BBB dysfunction produced by high cholesterol [295], oxidized low-density lipoprotein [334], sepsis, intracerebral hemorrhage [335, 336], or cerebral malaria [337]