Albumin and multiple sclerosis

Abstract

Leakage of the blood–brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furthermore, albumin binds metals and heme thereby limiting their ability to produce reactive oxygen and reactive nitrogen species. Albumin also has the potential to worsen disease. Similar to pathogenic processes that occur during epilepsy, extravasated albumin could induce the expression of proinflammatory cytokines and affect the ability of astrocytes to maintain potassium homeostasis thereby possibly making neurons more vulnerable to glutamate exicitotoxicity, which is thought to be a pathogenic mechanism in MS. The albumin quotient, albumin in cerebrospinal fluid (CSF)/albumin in serum, is used as a measure of blood-CSF barrier dysfunction in MS, but it may be inaccurate since albumin levels in the CSF can be influenced by multiple factors including: 1) albumin becomes proteolytically cleaved during disease, 2) extravasated albumin is taken up by macrophages, microglia, and astrocytes, and 3) the location of BBB damage affects the entry of extravasated albumin into ventricular CSF. A discussion of the roles that albumin performs during MS is put forth.

A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

“…APRIL present in reactive astrocytes may originate from infiltrating macrophages but also from the blood. The blood–brain barrier is permeable to serum components in MS, and myeloid cells constitutively secrete APRIL in the blood . These analyses demonstrate that APRIL acts locally on CNS‐resident astrocytes.…”

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

“…Increased CSF levels of albumin, IgG and other blood-derived proteins have also been reported in patients with ALS 62,224 . Qalb is also elevated in patients with MS 218 , and this change correlates with increased white matter BBB permeability detected by DCE-MRI 80 . In patients with HIV-1-associated dementia, increased Qalb was associated with axonal injury as measured by CSF levels of neurofilament light chain 225 .…”

“…However, CSF albumin levels could be influenced by proteolytic cleavage, as well as albumin uptake by brain macrophages, microglia, astrocytes, neurons, and oligodendrocytes (cells that express chondroitin sulfate proteoglycan 4 (also known as NG2)) 216–218 . Therefore, Qalb might underestimate the degree of BBB breakdown.…”

Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury

“…Whether these observations extend to other types of hepatotoxicity and whether long-term FcRn-albumin blockade would cause disadvantageous effects on the host need to be assessed in chronic models. It is of additional interest that, in certain conditions such as diabetes mellitus, posttranslational modifications of albumin are associated with toxicity; in such circumstances albumin elimination may also be desirable (57)(58)(59). Thus, in particular instances, acute albumin depletion might not be harmful and, as seen here, might prove beneficial, without conferring inordinate additional risk, when albumin is carrying toxic drugs or is modified in a pathological manner.…”