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.

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

“…Indeed, AD is associated with microvascular dysfunction, altered protein expression in particular Aβ transporters, LRP1 and RAGE, by endothelial cells and defective BBB that impact Aβ clearance (Zlokovic, ). Although the underlying mechanisms involved in BBB dysfunction are complex, oxidative stress and diverse inflammatory mediators seem to play a role (Zenaro, Piacentino, & Constantin, ). In this context, boldine treatment could improve BBB function by its protective action on endothelial cells and, as a consequence, could ameliorate Aβ clearance and reduce Aβ accumulation in boldine treated animals.…”

Rho‐associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

“…Peripheral immune cells such as monocytes and lymphocytes that are normally low in the parenchyma have increased numbers in the brains of AD patients and animal models (Zenaro et al . ). BBB disruption can stem from several possible events associated with AD.…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…Importantly, such damage may result from the presence of prolonged systemic inflammation and elevated levels of PICs, which increase the permeability of tight junctions by decreasing levels of glycocalyx and other adhesion molecules, as well as causing endothelial cell damage and disruption of the of glia limitans [385,386]. It is important to note that such damage may result from PICs in the systemic circulation or following activation of microglia and astrocytes in the brain and the latter phenomenon goes some way to explaining the dysfunction of the neurovascular unit seen in early AD patients described above [382,385,386].…”

“…Several authors have reported reduced expression of adhesion molecules and tight junction proteins in BBB endothelial cells combined with a dysfunctional and/or disrupted neurovascular unit in AD patients with early disease long before the occurrence of dementia and in the absence of neurodegeneration and brain atrophy [382][383][384]. Importantly, such damage may result from the presence of prolonged systemic inflammation and elevated levels of PICs, which increase the permeability of tight junctions by decreasing levels of glycocalyx and other adhesion molecules, as well as causing endothelial cell damage and disruption of the of glia limitans [385,386].…”