Reconsidering the role of blood-brain barrier in Alzheimer’s disease: From delivery to target

Abstract

The existence of a selective blood-brain barrier (BBB) and neurovascular coupling are two unique central nervous system vasculature features that result in an intimate relationship between neurons, glia, and blood vessels. This leads to a significant pathophysiological overlap between neurodegenerative and cerebrovascular diseases. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease whose pathogenesis is still to be unveiled but has mostly been explored under the light of the amyloid-cascade hypothesis. Either as a trigger, bystander, or consequence of neurodegeneration, vascular dysfunction is an early component of the pathological conundrum of AD. The anatomical and functional substrate of this neurovascular degeneration is the BBB, a dynamic and semi-permeable interface between blood and the central nervous system that has consistently been shown to be defective. Several molecular and genetic changes have been demonstrated to mediate vascular dysfunction and BBB disruption in AD. The isoform ε4 of Apolipoprotein E is at the same time the strongest genetic risk factor for AD and a known promoter of BBB dysfunction. Low-density lipoprotein receptor–related protein 1 (LRP-1), P-glycoprotein, and receptor for advanced glycation end products (RAGE) are examples of BBB transporters implicated in its pathogenesis due to their role in the trafficking of amyloid-β. This disease is currently devoid of strategies that change the natural course of this burdening illness. This unsuccess may partly be explained by our misunderstanding of the disease pathogenesis and our inability to develop drugs that are effectively delivered to the brain. BBB may represent a therapeutic opportunity as a target itself or as a therapeutic vehicle. In this review, we aim to explore the role of BBB in the pathogenesis of AD including the genetic background and detail how it can be targeted in future therapeutic research.

Patient-Derived Blood-Brain Barrier Model for Screening Copper Bis(thiosemicarbazone) Complexes as Potential Therapeutics in Alzheimer’s Disease

“…Here, we detected the potentially therapeutic immunomodulatory effects of selected Cu­(btsc) on AD iBEC, implicating additional neuroprotective mechanisms that may be involved at the level of BBB. Intriguingly, Cu­(btsc) were previously shown to exert therapeutic effects on preclinical models of AD, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD), as well as in first-in-human clinical trials targeting ALS and PD, all being neurodegenerative diseases with established roles in BBB neuroinflammation. − Correspondingly, with BBB disruption becoming in itself an emerging drug target in neurodegeneration, − further studies performed in our patient-derived model may support the ongoing efforts in identifying compounds that can improve cerebrovascular integrity in AD via active regulation of BEC and accelerate the translation of those therapies to patients.…”

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease

“…However, growing evidence suggests that AT‐secreted molecules, known as adipokines, may reach the systemic circulation and interact with the BBB and the neurovascular system, compromising its integrity and potentially influencing the development of neurological disorders including AD (Pan & Kastin, 2007). Also, breakdown of the BBB is an important pathological feature in AD, worsening the clearance of amyloid‐β (Aβ) peptides, microglial activation and astrogliosis (Sousa et al, 2023).…”

Blood–Brain Barrier Breakdown in Alzheimer’s Disease: Mechanisms and Targeted Strategies

“…Another genetic risk factor for AD is formin-related protein 2 (FMNL2), an astrogliaexpressed protein instrumental in glia-vasculature interactions and Aβ regulation [183]. Research indicated an elevated FMNL2 expression in both AD and cerebrovascular pathology [184]. Vascular risk factors amplify FMNL2 expression in AD patients, suggesting its pivotal role in exacerbating the AD pathology and vascular anomalies [185].…”

“…This amide enhances functional CBF responses following brain stimulation and cognitive processes and diminishes brain Aβ concentrations in an AD mouse model, specifically the APPsw−/+ mice [194]. Nevertheless, a Phase III clinical trial with a RAGE inhibitor (NCT02080364) was terminated due to its low efficacy [184]. Moreover, a randomized, double-blind, placebo-controlled study was conducted to assess PF-04494700, an oral RAGE inhibitor, in patients diagnosed with mild-to-moderate AD.…”