Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for AD pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD. Here, we showed dysfunctional BBB in AD patients reflected by perivascular accumulation of blood-derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin-5 and glucose transporter Glut-1 in the brain endothelial cells (BECs). In the APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and Aβ-treated BECs, we found suppressed Wnt/β-catenin signaling triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switching to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signaling) to activate Wnt/β-catenin pathway, BBB malfunction was restored by preventing Aβ-induced BEC impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate BBB malfunction induced by Aβ, which may be a potential treatment strategy for AD.

Intermittent Cytomegalovirus Infection Alters Neurobiological Metabolism and Induces Cognitive Deficits in Mice

“…This would be similar to a recent report showing CRISPR-Cas9 GLUT1 truncation decreased BMEC bioenergetics and negatively impacted neuro angiogenesis (Pervaiz et al, 2022). Expression of claudin-5, the dominant tight junction protein in the BBB, has been shown to decrease in parallel with GLUT1 following suppression of the Wnt/β-catenin pathway (Wang et al, 2022).…”

“…This would be similar to a recent report showing CRISPR-Cas9 GLUT1 truncation decreased BMEC bioenergetics and negatively impacted neuro angiogenesis (Pervaiz et al, 2022). Expression of claudin-5, the dominant tight junction protein in the BBB, has been shown to decrease in parallel with GLUT1 following suppression of the Wnt/β-catenin pathway (Wang et al, 2022). Our previous research has demonstrated that CMV infection dysregulates this pathway (Angelova et al, 2012; Zwezdaryk et al, 2016) providing a possible mechanism for these changes.…”

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

“…By linking white matter injury to cholesterol and Abeta metabolism and transport, we postulate that this helps explain why so many systemic factors increase the risk of AD. We postulate that the many AD risk factors act on white matter particularly with aging when the BBB is leakier (Methia et al, 2001;Ujiie et al, 2003;Zipser et al, 2007;Zlokovic, 2008;Deane et al, 2009;Farrall and Wardlaw, 2009;Jaeger et al, 2009;Lamartinière et al, 2018;Ma et al, 2018;Barisano et al, 2022;Wang et al, 2022c). Indeed, BBB dysfunction precedes amyloid plaque formation (Ujiie et al, 2003).…”

“…APOE deficiency compromises the BBB especially after injury, whereas APOE protects against neuropathology induced by high cholesterol diets and maintains the BBB during aging (Fullerton et al, 2001;Methia et al, 2001;Mulder et al, 2001). Abeta causes BBB dysfunction of vascular endothelial cells which is prevented by LRP6 activation of the Wnt/β-catenin pathways (Wang et al, 2022c).…”

Blood–brain barrier endothelial cells in neurodegenerative diseases: Signals from the “barrier”

“…For instance, increased remnants of capillaries, namely string vessels, are damaged vessels after BEC destruction, which have been reported in the AD brain for a long time (Brown, 2010).In vitro, different aggregation properties and heterogeneous compositions of Aβ peptides have distinct effects on endothelial cell viability, BBB integrity, and angiogenesis (Parodi-Rullan et al, 2020). Additionally, Aβ suppressed Wnt/β-catenin signaling by activation of GSK3β both in vivo and in vitro (Wang et al, 2022). The maintenance of BBB is dependent on the β-catenin signaling in BECs (Tran et al, 2016).…”