Front Cell Neurosci Review: Association between Aβ deposition and AD blood-brain barrier dysfunction

The production and deposition of amyloid-β (Aβ) is an important factor affecting the progression and prognosis of Alzheimer's disease (AD), which also leads to damage to the blood-brain barrier (BBB), which is also essential
for maintaining normal metabolism of Aβ.

A team of researchers from Tianjin Medical University published a review describing the characteristics of Aβ deposition and BBB damage in AD, summarizing their interactions, and detailing their respective mechanisms
.

01 The blood-brain barrier and Alzheimer's disease

BBB is a dynamic biological and physical barrier between the peripheral circulation and the central nervous system to maintain the normal function of neurons, transporters, and ion channels expressed on the BBB and involved in ion balance and synaptic function
.

BBB is composed of astrocytes, pericytes, and cerebral microvascular endothelial cells (BMECs), and Aβ destroys microvascular endothelial cells (BMECs) and tight junction (tj)-associated proteins, resulting in loss of BBB integrity
.

Figure 1.
Components of the blood-brain barrier and its performance in
different states.

02 Amyloid-β

Aβ accumulation triggers neurofibrillary tangles, oxidative stress, microglial activation, synaptic dysfunction, synaptic loss, and inflammatory responses
.
To prevent Aβ deposition, various Aβ scavengers in the brain work in synergy, including BBB trafficking, extracellular degradation of Aβ-proteolytic enzymes, cellular uptake, intracellular degradation, massive interstitial fluid (ISF) flow, and cerebrospinal fluid uptake (Figure 2).

Figure 2.
Production and clearance of Aβ in the brain

03 β amyloid deposition caused by blood-brain barrier dysfunction

Experiments have shown that BBB dysfunction leads to the deposition
of Aβ by increasing the production of Aβ and preventing its normal transport through BBB.
Many receptors regulate Aβ transport in the BBB, and the number and distribution of these receptors are affected by AD pathology, resulting in abnormal Aβ transport and deposition
.

(1) LDL receptor-related protein 1

LRP1, a member of the low-density lipoprotein receptor (LDLR) family, is involved in the process of
Aβ clearance.
Aβ can be reported to be exported from the brain via BBB via LRP1, which interacts with AβPP on the neuronal surface through its adaptor Fe65, thereby enhancing AβPP endocytosis and Aβ production
.

Figure 5.
LRP1 regulates a three-step mechanism for Aβ clearance

(2) Receptors for higher glycation end products

Advanced glycation end product receptor (RAGE) is a 35 kDa multi-ligand transmembrane receptor expressed
in neurons, vascular endothelial cells, and glial cells.
In the pathological state of neurodegenerative diseases, the expression level of RAGE is upregulated, and RAGE binds to ligands such as AGEs, Aβ, S100b, Mac-1, HMGB1, etc.
, and its expression level is determined
by the concentration of these ligands.

In AD, studies have shown that RAGE and Aβ binding leads to oxidative stress, decreased cerebral blood flow, and vascular
dysfunction.
In addition, the binding of RAGE and Aβ leads to the activation of microglia and the release of inflammatory factors, causing an inflammatory response and exacerbating the disruption
of brain homeostasis.

(3) P-glycoprotein (P-gP)

P-glycoprotein is a 140 kDa membrane protein that is a member
of the ATP-binding cassette (ABC) transporter superfamily.
In the brain, P-gP is primarily expressed on the surface of the BBB endothelial cavity (facing blood) and helps limit the use of ATP by brain-active drugs into the central nervous system
.
The expression and function of P-gP can be impaired
to varying degrees with age and progression of AD.

04 β Blood-brain barrier damage caused by amyloid deposition

During the occurrence and development of AD, the interaction of BBB dysfunction and Aβ deposition promotes neurodegenerative processes
.
Injection of soluble Aβ can damage BBB and lead to pericortical peripheral gliosis, and excessive Aβ production and deposition will increase the destruction of BBB, which plays a key role in the occurrence and development of AD, and the following are three possible mechanisms to explore
.

(1) Metalloproteinase (MMP)

Activated MMPs degrade extracellular matrix proteins, tight junction proteins, and basement membrane human vascular smooth muscle cells
.
In AD-associated BMC, the expression of MMP-2 and MMP-9 was increased, the expression of TJ-associated proteins such as CLDN-1 and CLDN-5 was minimal, and BBB permeability was significantly increased, and the silencing of MMP genes improved the permeability
of BBB.

(2) Reactive oxygen species (ROS)

Reactive oxygen species cause lipid peroxidation, activation of apoptosis, and local tissue damage, and both microdialysis administration of Aβ1–40 and intraventricular infusion of Aβ1–42 increase ROS levels
.
In addition, ROS induces phosphorylation of TJ proteins (CLDN-5, occludin, and ZO-1), which triggers a disruption
of BBB integrity.

(3) Nuclear factor-κB (NF-κB)

After entering the brain through the blood-brain barrier, Aβ deposition can activate NF-κB, promote the secretion of pro-inflammatory cytokines, and lead to neuroinflammation and the occurrence
of blood-brain barrier destruction.
In addition, the decomposition of BBB depends on the activation
of the Aβ-RAGE-NF-κB signaling pathway.

At present, the specific mechanism of Aβ damage to BBB is not enough and needs to be further explored, in addition to the association between Aβ and BBB mentioned in this paper, chronic neuroinflammation is also a hypothesis of the pathogenesis of AD, so gene editing and gene expression regulation have great potential
to regulate AD progression.