Fig. 5

BBB landscape across different neurodegenerative diseases. A), in physiological conditions the BBB is stable, which results in an adequate transport regulation that allows the brain homeostasis. B), Alzheimer’s disease severely affects the hippocampus and cortex, in those areas we have an accumulation of amyloid β plaques and TAU neurofibrillary tangles which can be released to the bloodstream, causing inflammation and oxidative stress, which can activate microglia and astrocytes. These stresses result in a loss of the BBB integrity, where there is cell death and loss of TJ. C), Parkinson’s disease most common areas that affect in the early stages are the substancia nigra (in pink) and the basal ganglia, it is known to accumulate both in neurons and astrocytes, damaging the neurons and causing the release of growth factors that can induce an angiogenesis response from the endothelium, which needs a loss of the TJ for the cells to migrate and form novel vessels. High levels of ROS are present in the bloodstream, which contributes to the BBB damage. D), Huntington’s disease has been shown to affect the basal ganglia and the brain cortex and in the context of the BBB, it causes the release of pro-inflammatory cytokines which can damage the brain endothelium. NRF2 protects the BBB in neurodegenerative diseases through various mechanisms. Aberrant protein aggregations generate ROS and inflammation, which NRF2 can suppress while promoting autophagy pathways to clear these aggregates. NRF2 also inhibits BACE1 gene expression, reducing Aβ protein release, and activates autophagy-related genes such as p62 and NDP52 to further support the removal of harmful protein accumulations. Macroautophagy is one main pathway, which is capable of removing neurofibrillary tangles, amyloid plaques, α-synuclein and huntingtin aggregates