The BBB’s Role in Multiple Sclerosis & Alzheimer’s Disease

The Blood-Brain Barrier’s Protective Role

The blood-brain barrier (BBB) is a complex structure in the brain’s blood vessels. It acts as a selective filter, controlling which molecules and cells can enter or leave the brain. By managing exchange between the central nervous system’s Cerebral Spinal Fluid (CSF) and the blood in general circulation, the BBB protects the brain and keeps the precise environment neurons and glial cells need.

When the BBB breaks down, it becomes more permeable. This lets circulating peripheral blood mononuclear cells (PBMC) and other molecules leak through that normally couldn’t. Because of this, BBB dysfunction is a major factor in many neurologic conditions, including Multiple Sclerosis (MS) and Alzheimer’s disease (AD).

BBB Breakdown in Multiple Sclerosis

In MS, CD4⁺ and CD8⁺ T-cells and B-cells infiltrate acute inflammatory lesions and areas of demyelination. Finding these immune cells there shows the BBB structure has changed enough to let them cross into the central nervous system (CNS).

Here’s how the damage builds:

• T-cells enter the CNS and release cytokines that inflame the endothelial lining (the cells that form blood vessels), creating perivascular lesions.
• This inflammation makes blood vessels in MS lesions display cell adhesion molecules (CAMs).
• CAMs bind to leukocytic integrins, letting immune cells stick to the inflamed vessels, cross the BBB, and move into surrounding tissue.

This becomes a vicious cycle. More immune cells activate in the CNS, which increases inflammation, which damages the BBB further and recruits more lymphocytes — including B-cells and cytotoxic T-cells. These eventually activate macrophages that destroy myelin. On top of that, monocytes that attach firmly to endothelial cells release reactive oxygen species (ROS), which may make the BBB even more permeable to T-cells and macrophages.

What triggers MS in the first place is still unclear. But many recent studies suggest BBB disruption happens early in MS lesion formation, followed by a wave of immune cells that destroy myelin and damage oligodendrocytes.

BBB Breakdown in Alzheimer’s Disease

Alzheimer’s patients show several problems in their brain blood vessels: damaged endothelial and pericyte cells, degenerating microvasculature, less glucose crossing the BBB, and abnormal inflammatory markers in the vessel walls. These changes are linked to β-amyloid peptide (Aβ) building up in the BBB’s vessel walls, which causes the loss of tight junction proteins. That loss disrupts the BBB and eventually triggers brain inflammation by activating microglia.

AD has two pathological hallmarks:

• More amyloid-β peptides (Aβ) — made from amyloid precursor protein (APP) — build up and form plaques in brain tissue.
• Tangles form inside neurons (neurofibrillary tangles, or NFTs), made of hyperphosphorylated tau protein. These cause the loss of synapses and neurons in affected brain regions.

Together with reduced Aβ clearance from the brain — which lets it build up outside cells and cause direct damage — these factors activate microglial cells. This inflammatory response releases neurotoxic cytokines that damage neurons’ internal skeletons, causing them to malfunction and eventually die.

Recent studies point to transforming growth factor-β1 (TGF-β1) as another player in BBB dysfunction in AD. TGF-β1 normally suppresses inflammation and controls microglial activation in the CNS. Studies show TGF-β1 signaling is significantly impaired in the AD brain. TGF-β1 may also reactivate astrocytes, which then produce more Aβ and worsen astrogliosis.

It’s still unclear whether these vascular changes cause AD or show up later in the disease. Either way, most Alzheimer’s patients have vascular damage, and go on to develop intracerebral hemorrhage and cerebral infarcts.

A Common Thread

Strong evidence points to BBB dysfunction as a factor in many neurologic disorders, including MS and AD. In both diseases, activated astrocytes interact closely with immune cells and blood vessels, driving BBB permeability even higher. Future research should focus on what triggers this inflammatory cascade in the first place, and on the damaging interactions between reactivated astrocytes and the endothelial cells that line the BBB.

Further Reading

Current and future treatments for Alzheimer’s disease. Yiannopoulou KG, PapageorgiouSG. (2013) Ther Adv Neurol Disord, 6(1) 19–33.

Neuroinflammation and blood–brain barrier changes in capillary amyloid angiopathy.Carrano A, Hoozemans JJ, van der Vies SM, van Horssen J, de Vries HE, Rozemuller AJ. (2012) Neurodegener Dis, 10:329– 331.