Tau Protein and Blood-Brain Barrier Dysfunction in Aging

Aggregation of phosphorylated tau protein into neurofibrillary tangles (and consequent toxicity leading to widespread cell death) is characteristic of late stage Alzheimer's disease, while dysfunction of the blood-brain barrier is a feature of aging thought to begin much earlier in the progression of the condition. The blood-brain barrier is a specialized set of cells lining the blood vessels of the central nervous system, allowing only certain molecules and cells to pass. When this barrier starts to leak, unwanted materials make their way into the brain, generating chronic inflammation and consequent issues in brain tissue. It is interesting to see discussion of potential effects of tau aggregation on blood-brain barrier leakage, as it wouldn't be the first significant causative mechanism that came to mind, given that tau is late and blood-brain barrier dysfunction is early in Alzheimer's disease. One could argue that tau aggregation and blood-brain barrier dysfunction are both downstream of chronic inflammation, while still being the case that both cause further chronic inflammation.

The blood-brain barrier (BBB) plays a crucial role in maintaining the specialized microenvironment of the central nervous system (CNS). In aging, the stability of the BBB declines and the permeability increases. The list of CNS pathologies involving BBB dysfunction is growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic, neuronal dysfunction, and detrimental neuroinflammatory changes. Such processes have been implicated in different diseases, including vascular dementia, stroke, Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus.

The BBB damage is also observed in tauopathies that lack amyloid-β overproduction, suggesting a role for tau in BBB damage. Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau (MAPT) in cells of the nervous system. Neuropathology of tauopathies is defined as intracellular accumulation of neurofibrillary tangles (NFTs) consisting of aggregated hyper- and abnormal phosphorylation of tau protein and neuroinflammation.

Disruption of the BBB found in tauopathies is driven by chronic neuroinflammation. Production of pro-inflammatory signaling molecules such as cytokines, chemokines, and adhesion molecules by glial cells, neurons, and endothelial cells determine the integrity of the BBB and migration of immune cells into the brain. The inflammatory processes promote structural changes in capillaries such as fragmentation, thickening, atrophy of pericytes, accumulation of laminin in the basement membrane, and increased permeability of blood vessels to plasma proteins. Here, we summarize the knowledge about the role of tau protein in BBB structural and functional changes.

Link: https://doi.org/10.3389/fnmol.2020.570045

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