UPS-mediated P-glycoprotein regulation in Alzheimer's disease: pharmacological implications for the amyloid pathology

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid β (Aβ), tau pathology, neuroinflammation, oxidative stress, and neurovascular dysfunction. Growing evidence suggests that impaired clearance of Aβ across the blood-brain barrier (BBB), rather than overproduction alone, is a key factor driving progression of AD. P-glycoprotein (P-gp) plays a crucial role in Aβ removal and is consistently reduced in AD. This review focuses on the mechanisms underlying P-gp dysfunction, particularly its regulation by the ubiquitin-proteasome system. Herein, we have discussed multiple factors associated with the AD, such as Aβ, oxidative stress, and inflammatory signaling, contributing to the phosphorylation, ubiquitination, internalization, and degradation of P-gp. These processes result in impaired transporter function and a compromised integrity of the BBB. The review further examines experimental and clinical evidence linking altered P-gp turnover with defective Aβ clearance in AD.