There is also initial evidence for possible causative role of a dysfunctional BBB in other neurodegenerative diseases. For instance, in an amyotrophic lateral sclerosis (ALS) mouse model, leakiness of the blood-spinal cord barrier owing to reduced expression of tight junctions and Glut1 precedes the onset of motoneuron degeneration (Garbuzova-Davis et al., 2011). However, deletion of mutant SOD in ECs in an ALS mouse model overexpressing mutant SOD attenuates BBB leakiness without improving survival selleck chemicals llc (Zhong et al., 2009) (Figure 6). The relevance of BBB abnormalities in ALS thus requires further elucidation. AD represents the prototypic example

of a dysfunctional neurovascular

unit. The main culprits are Aβ peptides, formed after cleavage of amyloid precursor protein (APP) by BACE (β-site AAP-cleaving enzyme) and subsequently γ-secretase. While mutations of these candidate genes result in increased Aβ production in rare familial cases, the more common late-onset sporadic form is caused by impaired Aβ clearance (Mawuenyega et al., 2010). Besides clearance via microglia and macrophages, Aβ is also transported across the BBB by LRP-1 or passively drained Cobimetinib in vitro along perivascular spaces (Bell and Zlokovic, 2009)—both mechanisms are impaired in AD. As a result of atherosclerotic or small vessel disease (conditions associated with AD), the vessel wall is stiffened, and pulsatile flow and perivascular fluid movement are reduced, impeding Aβ drainage. Aβ clearance is further compromised due to the vasoconstriction by hypercontractile SMCs and to the reduced endothelial LRP-1 expression, both resulting from overexpression of MyoCD and SRF (Bell et al., 2009 and Chow et al., 2007). Since short-term administration GPX6 of Aβ1-40 but not of the plaque-forming Aβ1-42 is known to induce oxidative damage of cerebral vessels and impair CBF (Iadecola, 2010), the resultant elevated Aβ levels will in turn cause vascular dysfunction (Figure 7). Eventually, Aβ accumulation in

the vascular wall, a condition referred to as cerebral amyloid angiopathy (CAA), destroys microvascular structure and function, leading to loss of the BBB integrity along with an inflammatory response, compromising neuronal viability. Since exposure of cultured neuronal cell lines to hypoxia or of mice to severe ambient hypoxia is capable of upregulating the expression of APP cleaving enzymes and transcription factors MyoCD and SRF, vascular insufficiency might further enhance amyloid production and compromise amyloid clearance, causing a vicious circle whereby Aβ accumulation aggravates vascular deficits and vice versa. However, whether sufficient hypoxia is present in early AD to upregulate these factors requires further study.