Circulating Claudin-5 Correlates with Age and Alzheimer's Disease

Researchers here demonstrate an association between increased claudin-5 levels in the bloodstream and age-related neurodegeneration. This is distinct from an underlying age-related decline in claudin-5 levels. The scientists do not speculate too deeply as to why this relationship might exist, but others have done so in the past. In short, claudin-5 is an important tight junction protein in the blood-brain barrier wrapping blood vessels that pass through the central nervous system. The blood-brain barrier prevents unwanted molecules and cells from passing to and from the brain. Dysfunction and leakage of the blood-brain barrier is characteristic of later life and neurodegenerative conditions, encouraging inflammation in brain tissue in response.

While claudin-5 is clearly necessary for blood-brain barrier function, it is an open question as to why exactly there is more of it in the bloodstream in the context of outright neurodegenerative disease versus the context of aging. Is some other form of disarray preventing it from integrating into the barrier when expressed, or is upregulation of expression a response to dysfunction in the blood-brain barrier, or is some other process at work under the hood?

The blood-brain barrier (BBB) plays pivotal roles in synaptic and neuronal functioning by sealing the space between adjacent microvascular endothelial cells. BBB breakdown is present in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). Claudin-5 (CLDN-5) is a protein essential for sealing the intercellular space between adjacent endothelial cells in the BBB. In this study, we developed a blood-based assay for CLDN-5 and investigated its diagnostic utility using 100 cognitively normal (control) subjects, 100 patients with MCI, and 100 patients with AD. Plasma CLDN-5 levels were increased in patients with AD (3.08 ng/mL) compared with controls (2.77 ng/mL).

The BBB functions as a selective gate for the uptake of essential molecules from blood into the brain and the excretion of harmful molecules from the brain into blood via transporters and receptors on cellular membranes. In addition, the BBB prevents the influx of blood-borne neurotoxins, cells, and pathogens into the brain because of the formation of tight junctions (TJs) in the intercellular space between adjacent macrovascular endothelial cells. Loss of BBB integrity has been observed in neuroinflammatory disorders, and patients with early AD demonstrate BBB leakage. In addition, patients with early cognitive dysfunction show BBB breakdown in the hippocampus, which occurs independently of brain accumulation of amyloid and tau. These several findings indicate that BBB TJ-sealing components might be impaired in MCI- and AD-related pathology.

Breakdown of the BBB, which is associated with CNS diseases, is accompanied by the invasion of leukocytes and activation of astrocytes. The matrix metalloproteinases (MMPs) secreted by these invading leukocytes have been shown to lead to the degradation of CLDN-5 in the BBB of mice. In a rat ischemic model, MMPs secreted from astrocytes likewise degraded CLDN-5 in the BBB. In addition, the number of pericytes in the BBB was greater in patients with AD compared with cognitively healthy peers, perhaps reflecting a response to endothelial breakdown. As is similar to our findings for patients with MCI or AD, circulating CLDN-5 levels are elevated in other CNS diseases, including ischemic stroke, bipolar disorder, and obsessive-compulsive disorder. The CLDN-5 circulating in blood might be derived from the endothelial cells in the BBB.

Interestingly, we found a significant negative association of plasma CLDN-5 level with age in MCI and AD. Ultrastructural analysis of TJ seals in the BBB did not reveal normal age-associated changes. In the current study, CLDN-5 levels were higher in younger than in older patients in both the MCI and AD groups. This is consistent with an analysis of autopsied brains which reported that the CLDN-5 level decreases with AD progression. Because reactive astrocytes and endothelial cells in the BBB in AD produce MMPs, prolonged activation of MMPs might lead to the degradation of CLDN-5 and, thus, lower plasma CLDN-5 levels in older compared with younger patients with cognitive deficits.


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