The blood-brain barrier in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by the pathological accumulation of amyloid beta (Aβ) peptides and neurofibrillary tangles containing hyperphosphorylated neuronal tau protein. AD pathology is also characterized by chronic brain inflammation, which promotes disease pathogenesis. In this context, the blood-brain barrier (BBB), a highly specialized endothelial cell membrane that lines cerebral microvessels, represents the interface between neural cells and circulating cells of the immune system. The BBB thus plays a key role in the generation and maintenance of chronic inflammation during AD. The BBB operates within the neurovascular unit (NVU), which includes clusters of glial cells, neurons and pericytes. The NVU becomes dysfunctional during AD, and each of its components may undergo functional changes that contribute to neuronal injury and cognitive deficit. In transgenic animals with AD-like pathology, recent studies have shown that circulating leukocytes migrate through the activated brain endothelium when certain adhesion molecules are expressed, penetrating into the brain parenchyma, interacting with the NVU components and potentially affecting their structural integrity and functionality. Therefore, migrating immune system cells in cerebral vessels act in concert with the modified BBB and may be integrated into the dysfunctional NVU. Notably, blocking the adhesion mechanisms controlling leukocyte-endothelial interactions inhibits both Aβ deposition and tau hyperphosphorylation, and reduces memory loss in AD models. The characterization of molecular mechanisms controlling vascular inflammation and leukocyte trafficking could therefore help to determine the basis of BBB dysfunction during AD and may lead to the development of new therapeutic approaches.

Keywords: Alzheimer's disease; Blood–brain barrier; Immune system cells; Leukocyte trafficking; Neurovascular unit; Vascular inflammation.

Fig. 1

Schematic cross-sectional representation of a cerebral capillary. Brain microvascular endothelial cells are the first barrier between blood vessels and brain parenchyma. Endothelial cells are linked by tight junctions (TJs), closely surrounded by pericytes and encircled by the basal lamina, which is contiguous with the plasma membranes of astrocyte endfeet and endothelial cells. Astrocyte endfeet processes support endothelial functions and provide the cellular link to neuronal cells. Ramified microglia can sense neuronal injury and release signals that are detrimental to the BBB.

Fig. 2

Schematic representation of neutrophil extravasation in postcapillary venules and potential CNS damage. Aβ and other inflammatory stimuli promote the activation of cerebral endothelium and immune system cells. The activated endothelium in brain venules upregulates the expression of adhesion molecules and chemoattractants supporting the adhesion of neutrophils that transmigrate into the brain parenchyma. Neutrophils adhered on activated endothelium may acquire a toxic phenotype, releasing reactive oxygen species (ROS), cytokines, chemokines and enzymes contributing to the destruction of the BBB. Neutrophils may also release neutrophil extracellular traps (NETs) comprising decondensed chromatin and active proteases that may damage the BBB. Migrated neutrophils and microglia may sustain their reciprocal activation, resulting in chronic inflammation and neuronal degeneration. Intraparenchymal neutrophils may be toxic towards neuronal and glial cells and may promote synaptic dysfunction, Aβ deposition and tau hyperphosphorylation.

Fig. 3

Leukocytes migrate in the brain of mice with AD-like disease. Confocal microscopy images of CD45⁺ leukocytes (red cells) localized in the cortex (A) and choroid plexus (B) of sex/age-matched wild-type control animals (left panels) and 3xTg-AD mice (right panels) at 6 months of age. Nuclei are stained with DAPI in blue. Scale bars = 30 μm.