Blood–Brain Barrier Breakdown in Alzheimer’s Disease

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This entry is adapted from the peer-reviewed paper 10.3390/ijms242216288

The blood–brain barrier (BBB) is a unique and selective feature of the central nervous system’s vasculature. BBB dysfunction has been observed as an early sign of Alzheimer’s Disease (AD) before the onset of dementia or neurodegeneration. The intricate relationship between the BBB and the pathogenesis of AD, especially in the context of neurovascular coupling and the overlap of pathophysiology in neurodegenerative and cerebrovascular diseases, underscores the urgency to understand the BBB’s role more deeply. Preserving or restoring the BBB function emerges as a potentially promising strategy for mitigating the progression and severity of AD. Molecular and genetic changes, such as the isoform ε4 of apolipoprotein E (ApoEε4), a significant genetic risk factor and a promoter of the BBB dysfunction, have been shown to mediate the BBB disruption. Additionally, receptors and transporters like the low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), and the receptor for advanced glycation end products (RAGEs) have been implicated in AD’s pathogenesis.

Alzheimer’s disease blood–brain barrier BBB

1. Introduction

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that predominantly affects the elderly, leading to cognitive decline, memory loss, and an impaired daily functioning ^[1]. As the most common cause of dementia, AD accounts for 60–80% of all cases, making it a significant health concern and the sixth leading cause of death for Americans aged 65 and above ^[2], with an estimated 6.7 million Americans are currently living with the disease ^[3]. Furthermore, with the aging of the global population, the prevalence of AD is on the rise, positioning AD as a formidable global healthcare challenge. In light of this growing health concern, the U.S. Food and Drug Administration (FDA) has granted an accelerated approval to a novel treatment of AD, Aducanumab, and the full approval to Lecanemab. These drugs are monoclonal antibodies targeting amyloid beta (Aβ) that is implicated in the AD pathology ^[4]^[5]. However, the other used medications, including the acetylcholinesterase inhibitors (galantamine, rivastigmine, and donepezil) and the N-methyl-D-aspartate (NMDA) antagonist, i.e., memantine, only provide symptomatic relief by improving memory and the ability to perform daily functions without curing the disease ^[6].

AD comprises two primary neuropathological hallmarks: extracellular amyloid-β (Aβ) accumulation and aggregated neurofibrillary tangles (NFTs) that are spread across the brain ^[7]. These pathological events induce neuronal atrophy and synaptic loss, culminating in neurodegeneration. Multiple hypotheses have been formulated to explain the development of AD, including the amyloidogenic cascade, tauopathy, neurovascular dysfunction, oxidative stress, and neuroinflammation ^[8]. Out of these, neurovascular dysfunction has received significant importance; several studies have implied that neurovascular dysfunction plays a vital role in the initiation and progression of AD, which suggests an association between alterations in cerebrovascular function and neurodegeneration ^[9]. In line with this, the two-hit vascular hypothesis of AD suggests cerebrovascular damage (hit 1) as an initial insult that is self-sufficient to initiate neuronal injury and neurodegeneration. Additionally, it promotes the buildup of Alzheimer’s Aβ toxin in the brain (hit 2) ^[10].

It is crucial to highlight the role of genetic factors in neurovascular dysfunction and their consequential influence on the development and progression of AD and cerebral amyloid angiopathy (CAA). CAA is a progressive Aβ build-up in the walls of small leptomeningeal and cortical arteries and cortical capillaries ^[11]. Amyloid plaques from CAA tend to accumulate in cortical and leptomeningeal vessels, whereas those caused by AD gather in the parenchyma ^[12]. The ε4 allele of the apolipoprotein E (ApoE) gene (ApoEε4) plays a crucial role in Aβ deposition as a senile plaque. It is associated with brain vascular damage, leading to AD and CAA pathogeneses ^[13]^[14]. Moreover, AD patients with homozygous ApoEε4 exhibit thinner capillary basement membranes and an increased plasma protein leakage into the cortex ^[15]. The ApoEε4 isoform has been linked to the blood–brain barrier (BBB) breakdown, reduced cerebral blood flow (CBF), neuronal loss, and behavioral deficits independent of Aβ ^[16].

The BBB dysfunction is increasingly recognized as a significant factor contributing to AD ^[17]. It has been suggested that the BBB breakdown may precede cognitive decline and neurodegeneration, highlighting the critical need for further exploration of the BBB’s role in AD and its potential as a therapeutic target ^[17]. The BBB endothelium is a specialized system of brain microvascular endothelial cells that separate circulating blood from the brain’s extracellular fluid, maintaining the brain’s homeostatic environment ^[18]. The BBB endothelium plays a crucial role in the protection and functioning of the brain, allowing the selective passage of nutrients and molecules essential for brain function while simultaneously preventing the entry of potentially neurotoxic substances ^[17].

2. NVU and the BBB

A schematic presentation of the NVU and the BBB are shown in Figure 1. The NVU is a crucial anatomical and functional unit that safeguards the homeostasis and optimal functioning of the central nervous system (CNS) ^[19]. Comprising several cell types, the NVU forms an interactive and dynamic system with its cellular constituents (Figure 1A). Neurons, the principal functional entities orchestrating signal transmission throughout the nervous system, are essential for the NVU ^[20]. Their close interaction with astrocytes, star-shaped glial cells, is pivotal for maintaining extracellular ion balance, facilitating synaptic transmission, and regulating CBF ^[21]. Microglia, the CNS’s resident immune cells, continually patrol the neural milieu and are ready to respond to alterations or threats ^[22]. Microglia participate in inflammatory responses and contribute to the NVU’s overall functionality by interacting with other cellular entities, including neurons and astrocytes ^[23].

Figure 1. Schematic representation of the NVU (A) and the BBB (B). B is a magnification of the Box surrounding the capillary in A to demonstrate the cellular components of the BBB. The Box in B is magnified to show the connection between endothelial cells represented by tight and adherence junctions.

The extracellular matrix (ECM), a non-cellular component of the NVU, provides structural support and influences cellular functions, including cell adhesion, migration, differentiation, and proliferation ^[24]. The NVU further comprises pericytes and endothelial cells, which are critical cellular components and contributors to the BBB’s integrity and function ^[25]. Pericytes, encapsulating the endothelial cells within capillaries, play a key role in vascular stability, angiogenesis, and the BBB’s permeability ^[26].

The BBB is a highly selective semipermeable barrier crucial in maintaining brain homeostasis ^[17]^[27]. BBB acts as an essential protective and regulatory shield for the CNS, restricting the entry of neurotoxic substances from the blood circulation ^[28]. The BBB is more than a passive barrier; it performs a dynamic orchestration of the CBF to meet the metabolic demands of the neurons ^[29]. Its role is not only limited to maintaining CNS homeostasis by regulating crucial nutrients such as glucose and oxygen but also includes the selective removal of metabolic waste products from the brain ^[30].

The endothelial cells of the BBB are interconnected to form a polarized monolayer with unique luminal (apical) and abluminal (basolateral) compartments separating the brain parenchyma from the peripheral system (Figure 1B) ^[28]. These distinct compartments play a critical role in maintaining the physical and functional integrity of the BBB ^[28]^[31]. The endothelial cells contribute significantly to the BBB functionality ^[28]. Primarily, on the apical side, the membrane connecting CNS endothelial cells creates a paracellular barrier, restricting the diffusion of small hydrophilic molecules and ions ^[28]^[32]. Secondly, the passive and active receptors, channels, and transport proteins located on the luminal and abluminal sides govern the transportation of endogenous molecules into and out of the brain. Lastly, the endothelial cells function as a communication medium between the CNS and the peripheral system by controlling the migration of circulating immune cells into the brain’s microenvironment ^[28]^[32].

3. BBB Dysregulation with Aging

The dysregulation of BBB in aging involves both a loss of selective transport mechanisms and a reduction in structural integrity ^[33]. This is exemplified by a global shift in the pattern of protein transcytosis, transitioning away from a receptor-mediated transport (RMT) to an increased caveolar transcytosis, which allows the entry of potentially neurotoxic proteins such as albumin and fibrinogen that are otherwise restricted in youth ^[33]^[34]. This change in the BBB’s permeability is implicated in the pathophysiology of neurodegenerative diseases, including AD, by facilitating neuroinflammation through unregulated protein entry ^[35]^[36]. Moreover, the age-related decrease in pericyte coverage further compromises the BBB, impairing blood flow and neuronal function ^[37]. The observed upregulation of endothelial alkaline phosphatase, namely ALPL, in AD patients, suggests it to be a potential therapeutic target, as its inhibition could modify the BBB’s permeability and influence the disease progression ^[38]. Overall, these changes underscore a “two-hit” hypothesis for vascular contributions to AD, where both pericyte loss and dysfunctional transcytosis act synergistically with other pathogenic factors like Aβ accumulation. Understanding the evolving nature of the BBB’s communication with the periphery is crucial for deciphering the impact of aging on the brain in health and disease ^[38].

4. BBB Dysfunction in AD

4.1. Effect of Comorbidities on BBB

The BBB disruption is related to multiple comorbidities, including vascular comorbidities such as atherosclerosis, where both diseases are characterized by inflammation and vascular dysfunction ^[39]. Small vessel dysfunction is responsible for the BBB breakdown, CBF and Aβ clearance reduction, and neuronal dysfunction ^[39]^[40]. However, findings from the Baltimore Longitudinal Study of Aging (BLSA) Cohort, which investigated the relationship between Alzheimer’s and atherosclerosis, found no association between the degree of Alzheimer’s pathology and atherosclerosis in the aorta, heart, and intracranial vessels, though only intracranial atherosclerosis correlated with dementia ^[41].

Moreover, comorbidities, including Type 2 Diabetes Mellitus (T2DM), hypertension, obesity, sleep disorders, and hypercholesterolemia, are increasingly recognized as contributing factors in the disruption of the BBB and the progression of AD ^[42]^[43]. In the case of T2DM, which is characterized by insulin resistance and chronic hyperglycemia, it causes endothelial dysfunction and inflammation that could ultimately compromise the BBB’s integrity. These alterations potentially facilitate the entry of neurotoxic molecules like Aβ, thereby contributing to AD pathology ^[44]^[45].

Obesity, especially as a part of the metabolic syndrome, often precipitates systemic inflammation and endothelial dysfunction, contributing to a compromised BBB function ^[46]. Sleep disorders, particularly those impacting the glymphatic system, are emerging as critical players in hindering the efficient clearance of neurotoxic products such as Aβ, ultimately fostering an environment conducive to AD progression ^[47].

The cumulative impact of these comorbidities cannot be overlooked, as they often co-occur and may have synergistic effects on BBB dysfunction and AD pathology. These comorbidities exacerbate the degradation of TJs, thereby compounding the risk of BBB dysfunction and the subsequent development and progression of AD ^[48]^[49]^[50]^[51]. The interplay between the degradation of TJs by proteases and the risk factors for AD suggests a vicious cycle where the compromised barrier function of the BBB can lead to further neuronal damage and progression of AD. At the same time, the disease state promotes a further BBB breakdown ^[51].

4.2. ApoE and BBB Dysfunction in AD

ApoE is mainly expressed in astrocytes and microglia in the brain; its functions are associated with the endocytosis of lipoproteins, the deposition and transport of Aβ, membrane integrity, neurotoxicity, and synaptic plasticity ^[14]. It is produced in the brain, liver, kidneys, skin, adipose tissue, and many other organs ^[52]. Within the CNS, ApoE is produced de novo separately and independently from peripheral ApoE ^[53].

ApoE protein has three different isoforms: ApoEε2, ApoEε3, and ApoEε4. These isoforms have functional and structural differences, inconsistencies, and discrepancies in their interaction with low-density lipoprotein (LDL) receptors ^[52]. Within the cell, ApoE plays a role in cellular processes involving the maintenance of the cytoskeleton, mitochondria, and dendrites, leading it to play a prominent role in the overall health of neurons ^[52]. ApoE amino acids vary at locations 112 and 158 on chromosome 19, and there are six different genotypes, i.e., three homozygous and three heterozygous ^[54]. ApoEε2 is protective against the pathology of AD ^[55]. ApoEε2 expression clears Aβ normally and may suppress inflammation, which can protect against AD ^[54].

To investigate the role of ApoEε2 in AD, using post-mortem human cortices, Fernández-Calle, and colleagues reported that the abundance of ApoEε2 and its ability to bind to LDLRs increased the efficiency of Aβ clearance. In addition, they found that the expression of mRNA molecules related to ECM increased, which could contribute to the protection of the BBB’s integrity. These effects of ApoEε2 point toward its protective abilities against AD ^[56]. ApoEε3, the most common form of the gene, on the other hand, does not present a risk for or protection from AD relative to the ε4 and ε2 alleles, respectively. ApoEε3 protein functions well in binding to LDL, very low-density lipoprotein (VLDL), and low-density lipoprotein-related protein-1 (LRP1) receptors, which play a role in clearing Aβ ^[56].

The most heavily researched isoform is ApoEε4. ApoEε4 is associated with an earlier onset of AD due to a higher plaque density earlier in life ^[14]. ApoEε4 likely contributes to AD pathology by increasing neurotoxicity and decreasing the protection of the CNS ^[53]. However, the mouse apoE gene exists only in one isoform and is located on chromosome 7 rather than 19. For this reason, mice are often artificially introduced to human ApoE to make the study applicable to human AD ^[56]. ApoEε4 correlates with a decreased BBB integrity and cognitive impairment due to disturbed homeostasis and neurotoxin extravasation into the brain ^[57]. ApoEε4 knock-in mice displayed the loss of pericytes and a subsequent BBB degradation as they aged ^[58]. This loss of pericytes was also found in human ApoEε4 carriers ^[53].

4.3. Tight Junctions’ Role in BBB Health and Disease

The barrier function of TJs in the BBB is multifaceted. They restrict the intercellular space, preventing the unregulated diffusion of substances between the blood and the brain. This role is critical in preserving the specialized environment required for an optimal neural function ^[59]. Concurrently, TJs maintain cellular polarity by ensuring an asymmetrical distribution of proteins across the cell, a decisive factor for a directional transport across the endothelium ^[59]. On the paracellular front, TJs exert tight control over the diffusion pathways by leveraging an array of integral proteins, such as claudins, occludin, and JAMs. The specific assembly of these proteins determines the permeability properties of the junctions, allowing selective passage of ions and molecules while safeguarding against harmful substances ^[60]. For the transcellular route, the asymmetrical distribution of transporters and channels underpins a regulated transport mechanism, ensuring that essential nutrients reach the brain while metabolic waste products are efficiently evacuated. The concerted action of these transcellular elements with TJs establishes the BBB as a dynamic regulatory interface, which is adept at adjusting to physiological needs and protecting against pathological insults.

In AD, one of the critical pathways by which TJs can be compromised involves the activity of matrix metalloproteinases (MMPs) and other proteases ^[61]. MMPs are a family of zinc-dependent endopeptidases capable of degrading various components of the extracellular matrix (ECM). They are known to modulate the permeability of the BBB by targeting TJ proteins ^[62]. MMPs, particularly MMP2 and MMP9, have been demonstrated to cleave occludin, claudins, and ZO proteins, leading to the disassembly of TJs and an increased BBB permeability ^[62]. The activity of MMPs is tightly regulated under normal physiological conditions but can be upregulated in response to inflammation, ischemia, and oxidative stress, which are common in the AD pathology ^[61].

4.4. Transporters’ Role in BBB Health and Disease

The functionality of the BBB is partly enabled by the presence of diverse influx and efflux transporters expressed in the endothelial cells, notably from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies ^[63]^[64]^[65]. The BBB restricts drug access to the brain by permitting only lipophilic molecules of low molecular weight into the brain via the transcellular pathway from the bloodstream, where most researchers consider a cut-off point of 400–600 kDa. However, deviations from this cut-off point have been published ^[66]. Small, lipid-soluble drugs, such as antidepressants, penetrate the BBB via passive diffusion across the BBB ^[31]. Transcytosis transports macromolecules, such as insulin and amino acids ^[31]. Efflux transporters counteract the passive diffusion by forcing foreign substances, toxic metabolites, and other waste products out of the brain ^[31].

In contrast, recombinant proteins, therapeutic antibodies, and nucleic acid drugs are too large to cross the BBB ^[31]. The BBB disruption could be due to, at least in part, the modulation of transporters’ function or expression, accumulating waste products, and the inadequate nutrient delivery to the brain ^[31]. Overall, more than 50 transporters are expressed in the BBB, and their modulation by aging or AD could alter the BBB function, thus contributing to AD pathology ^[67].

5. BBB Breakdown Mechanisms

A schematic presentation of the discussed mechanisms is presented in Figure 2. The disruption of the BBB could impair any of the NVU cellular components. The disruption of endothelial cells might result in a decreased TJs’ expression. It has been shown that occludin, claudin-5, and ZO1 expressions are lower in the Aβ-laden capillaries of patients with capillary CAA ^[31], implying that reduced TJs may increase the vascular permeability in an AD brain. Multiple cellular signaling pathways, such as calcium signaling, could mediate the disruption of TJs. In AD, the RAGE–Aβ₄₂ interaction disrupts TJs via a calcium-calcineurin signaling pathway ^[68]. In addition, in the monolayer culture of bEnd3 cells, adding Aβ₄₂ induces structural alterations in ZO1 ^[68]. Other TJ proteins, such as claudin-5 and occludin, were also structurally altered, and their expression was reduced by Aβ₄₂ ^[68]. This result was confirmed as neutralizing antibodies against RAGEs and calcineurin and MMP inhibitors prevented Aβ₄₂-induced changes in the ZO1 expression ^[68]. Furthermore, the expression of TJs is negatively correlated with Aβ₄₀ levels in cortical areas and positively correlated with synaptic markers in patients with AD, highlighting the role of TJs in the AD pathology development ^[69].

Figure 2. A representative scheme demonstrates a healthy BBB and a dysfunctional BBB.

Transport protein expression alterations in endothelial cells could be a mechanism or a consequence of BBB disruption ^[70]. In AD, the failure of Aβ clearance through transport across the BBB is caused by decreased levels of LRP1 and P-gp and an increased RAGE expression. For example, in an in vitro experiment, a high cholesterol level decreased the LRP1 expression, increased the RAGE expression, and increased Aβ40 levels in cerebral microvascular endothelial cells ^[71]. Other transport disruptions include a reduced expression of the GLUT1 transporter ^[70]^[72]. This effect was seen with a lower expression of GLUT1 in endothelial cells but not in astrocytes of the BBB in GLUT1-deficient APP_sw-mice ^[73]. The LRP1 protein is vital to maintain the BBB’s integrity; it acts as a co-activator of peroxisome proliferator-activated receptor gamma (PPARγ), transports cholesterol associated with ApoE ^[74], plays a role in glucose metabolism ^[75], and interacts with Aβ to transport it across the BBB ^[74]. The LRP1 activation can stimulate PPARγ and increase TJs’ expression. This effect has been investigated in mouse models where a selective brain endothelial LRP1 knockout reduced the expression of TJ proteins and P-gp, increased the MMP activity, and decreased the TEER, leading to endothelial cell disruptions ^[76]. Endothelial cell disruption causes neuroinflammation due to neurotoxic substances infiltrating into the brain, causing inflammation and neurodegeneration. Fibrinogen leakiness in the brain activates the macroglia and initiates inflammation ^[77]^[78].

Aside from endothelial cell disruptions, neuroinflammation and the activation of glial cells can further drive AD pathology. Microglial activation can release pro-inflammatory factors, resulting in neuroinflammation ^[79]. Although inflammation is a protection mechanism, an overly aggressive inflammatory response can cause or contribute to tissue damage. In AD, astrocyte degeneration causes the BBB disruption. Using tamoxifen-astrocyte-depleted mice, large molecules such as fibrinogen and smaller molecules such as cadaverine, an exogenous labeled small molecule, were detected in the brain as soon as the astrocytes were depleted, which was accompanied by reduced levels of TJ proteins, and lower expression of GLUT1 ^[80]. Aquaporin-4 (AQP-4), a water channel facilitating bidirectional water transfer, is expressed by astrocytes at the BBB ^[81].

The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome has a significant role in AD-related neuroinflammation. The interaction of Aβ with astrocytes and macroglia can activate NLRP3 inflammasome, causing the release of chemokines and inflammatory mediators and activating the caspase-1 cascade ^[82]. The activation of NLRP3 inflammasome results in the BBB breakdown by the generated cytokines, whereas reducing the inflammasome activation reduces the inflammatory response and improves the BBB function ^[83]. NF-κB is another inflammatory transcription factor that is increased in AD. The activation of NF-κB by Aβ plaques, NFT, or oxidative stress causes the release of proinflammatory cytokines and ROS and promotes neuroinflammation. Like neuroinflammation, oxidative stress plays a significant role in the BBB disruption ^[79]. Oxidative stress is a condition produced by an imbalance between the generation and accumulation of ROS in cells and tissues and the ability of a biological system to detoxify these reactive products ^[84]. Neuroinflammation and oxidative stress result in neuronal cell death, altered neurotransmitter production and activity, and decreased synaptic functioning, all of which can lead to cerebral injury and dysfunction ^[85]^[86].

In AD, Aβ deposits cause pericyte degeneration ^[87]^[88]. Aβ-pericytes signaling causes vascular constriction and decreases CBF through ROS generation in humans and rodents ^[89]. This degeneration is affected by the ApoE isoform where ApoEε4 accelerates the BBB breakdown; ApoEε4 also reduces the calcineurin–nuclear factor of activated T cells (NFAT) signaling in pericytes and causes the BBB disruption ^[90]. ApoEε4 iPSC-derived-mural cells expressed higher levels of cytoplasmic and nuclear NFATc1 protein and exhibited a higher gene expression of calcineurin catalytic subunits (PPP3CA and PPP3CC). Increased levels of NFATc1 induce the CAA pathology by interacting with ApoEε4 promoter in ApoEε4-expressing pericytes. Inhibiting calcineurin in iPSC-derived mural cells reduced ApoE expression in ApoE4-expressing cells and NFATc1 in ApoE3-expressing cells ^[90].

In AD, the dysfunction of the Wnt/β-catenin signaling pathway has been associated with the BBB breakdown. Under normal conditions, Wnt/β-catenin signaling is essential for the CNS angiogenesis ^[91]. Reduction in this signaling pathway reduces the expression of TJs and modulates the expression of transporters such as P-gp and GLUT1, leading to an increased BBB permeability ^[91]. Suppressing Wnt/β-catenin signaling in the APP_swe/PS1_dE9 (APP/PS1) microvessels increased glycogen synthase kinase-3 beta (GSK-3β), whereas its activation, using LRP6-optogenetic tool, restored the BBB TJs, and prevented Aβ-induced endothelial cells’ dysfunction ^[92]. The same effect has been shown in human iPSCs where the activation of the Wnt/β-catenin pathway using CHIR 99021 (CHIR), an inhibitor of GSK-3β and an agonist of Wnt/β-catenin, induced GLUT1 and claudin-5 expressions, and downregulated levels of plasma lemma vesicle-associated protein (PLVAP) ^[93]. Wnt/β-catenin signaling also regulates paracellular and transcellular permeabilities ^[94].

The genetic underpinnings of the BBB dysfunction in AD provide a fascinating, yet relatively understudied, angle to the ongoing research in the field. A significant proportion of genes implicated in the AD risk have been linked to the brain’s vascular and perivascular systems, further suggesting the integral role of the BBB’s integrity in the AD pathogenesis. The human brain vasculature expresses 30 out of the top 45 genes linked to the AD risk based on genome-wide association studies (GWAS) ^[95]. Remarkably, several genes identified in GWAS, including PICALM, known for its involvement in endocytosis facilitating the internalization of cell receptors, have variants that can increase the Aβ accumulation in the brain, exacerbating the AD pathology ^[96], as shown by triggering clathrin-mediated endocytosis through its interaction with LRP1 ^[97].

Mutations in the OCLN gene, responsible for encoding occludin ^[98], and the junctional adhesion molecule-C (JAM-C) gene, responsible for encoding the junctional molecule JAM-C, are directly implicated in the compromise of the BBB’s integrity ^[99]^[100]. Furthermore, NOTCH3 gene, vital for vascular integrity through smooth muscle cell differentiation, presents mutations that affect blood vessel walls and the BBB’s integrity, further linking it to AD and vascular dementia ^[101]. Mice with the CADASIL-associated Notch3-R169C mutation exhibit an accumulation of the NOTCH ectodomain within pericytes. This accumulation is concomitant with the pericyte degeneration and a subsequent compromise of the BBB’s integrity ^[102].

TREM2, which encodes the triggering receptor expressed on myeloid cells 2 protein, was highlighted as an AD susceptibility gene in two GWAS ^[103]^[104]. Notably, these studies identified the R47H missense mutation, which presents a heightened AD risk comparable to possessing one ApoEε4 allele ^[103]. Predominantly expressed in brain microglia, TREM2 is pivotal in mediating the neuroinflammatory reactions associated with AD ^[105]. In-depth functional analyses of TREM2 have elucidated its involvement in the modulation of Aβ plaque accumulation in brain parenchyma, the advancement of tau-related pathology, and BBB dysfunction ^[104]^[106]^[107]^[108]. TREM2 may affect the integrity of the BBB by affecting inflammation, the microglial oxidative response, and insulin resistance. Moreover, many studies have found that soluble TREM2 (sTREM2) may disrupt the BBB’s integrity in AD by interacting with pro-inflammatory proteins such as TNF receptor 1 and TNF receptor 2, and their effectors like intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 ^[109].

6. The BBB as a Therapeutic Target

The BBB dysfunction has been implicated in the pathogenesis of AD and many other neurodegenerative diseases ^[25]^[110]. While there are new medications targeting Aβ, such as the recent FDA-approved monoclonal antibody Lecanemab, a curative therapy for AD remains elusive. Furthermore, these medications are associated with severe adverse reactions, including edema and cerebral microhemorrhages ^[111]. Such concerns underscore the potential need for combined therapies that simultaneously address the BBB function and other key aspects of AD. Accordingly, there has been a growing interest in developing therapeutic strategies that target the BBB to enhance drug delivery, improve the clearance of toxic molecules, and restore the barrier function ^[112]. Strategies to modulate the BBB function in AD can be broadly categorized into three main areas: enhancing the Aβ clearance across the BBB, improving the BBB’s integrity and function, and addressing neuroinflammation ^[25]^[110]. Indeed, the intricate regulation of Aβ transporters, both influx and efflux, plays a crucial role in the Aβ accumulation. The dysregulation of these transporters has been recognized as a potential therapeutic target of AD ^[112].

References

DeTure, M.A.; Dickson, D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 2019, 14, 32.
Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2019, 15, 321–387.
Alzheimer’s association. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement 2023, 19, 1598–1695.
FDA. FDA Grants Accelerated Approval for Alzheimer’s Disease Treatment. Available online: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment (accessed on 15 May 2023).
FDA. FDA Grants Accelerated Approval for Alzheimer’s Drug. Available online: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug (accessed on 15 May 2023).
Marucci, G.; Buccioni, M.; Dal Ben, D.; Lambertucci, C.; Volpini, R.; Amenta, F. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 2021, 190, 108352.
Serrano-Pozo, A.; Frosch, M.P.; Masliah, E.; Hyman, B.T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2011, 1, a006189.
Andrade-Guerrero, J.; Santiago-Balmaseda, A.; Jeronimo-Aguilar, P.; Vargas-Rodríguez, I.; Cadena-Suárez, A.R.; Sánchez-Garibay, C.; Pozo-Molina, G.; Méndez-Catalá, C.F.; Cardenas-Aguayo, M.-d.-C.; Diaz-Cintra, S. Alzheimer’s Disease: An Updated Overview of Its Genetics. Int. J. Mol. Sci. 2023, 24, 3754.
Nelson, A.R.; Sweeney, M.D.; Sagare, A.P.; Zlokovic, B.V. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim. Biophys. Acta 2016, 1862, 887–900.
Li, S.; Wang, C.; Wang, Z.; Tan, J. Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer’s disease: An adrenergic approach. Aging Albany NY 2021, 13, 21791–21806.
Ringman, J.M.; Sachs, M.C.; Zhou, Y.; Monsell, S.E.; Saver, J.L.; Vinters, H.V. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease. JAMA Neurol. 2014, 71, 878–883.
Theodorou, A.; Tsantzali, I.; Kapaki, E.; Constantinides, V.C.; Voumvourakis, K.; Tsivgoulis, G.; Paraskevas, G.P. Cerebrospinal fluid biomarkers and apolipoprotein E genotype in cerebral amyloid angiopathy. A narrative review. Cereb. Circ.-Cogn. Behav. 2021, 2, 100010.
Liu, C.C.; Liu, C.C.; Kanekiyo, T.; Xu, H.; Bu, G. Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat. Rev. Neurol. 2013, 9, 106–118.
Kim, J.; Basak, J.M.; Holtzman, D.M. The role of apolipoprotein E in Alzheimer’s disease. Neuron 2009, 63, 287–303.
Salloway, S.; Correia, S.; Peck, J.; Harrington, C. Dementia with Lewy bodies: A diagnostic and treatment challenge. Med. Health Rhode Isl. 2002, 85, 207–209.
Montagne, A.; Nikolakopoulou, A.M.; Huuskonen, M.T.; Sagare, A.P.; Lawson, E.J.; Lazic, D.; Rege, S.V.; Grond, A.; Zuniga, E.; Barnes, S.R. APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β. Nat. Aging 2021, 1, 506–520.
Zlokovic, B.V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008, 57, 178–201.
Abbott, N.J.; Rönnbäck, L.; Hansson, E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 2006, 7, 41–53.
Zhao, Z.; Nelson, A.R.; Betsholtz, C.; Zlokovic, B.V. Establishment and dysfunction of the blood-brain barrier. Cell 2015, 163, 1064–1078.
Guttenplan, K.A.; Liddelow, S.A. Astrocytes and microglia: Models and tools. J. Exp. Med. 2019, 216, 71–83.
Verkhratsky, A.; Nedergaard, M.; Hertz, L. Why are astrocytes important? Neurochem. Res. 2015, 40, 389–401.
Prinz, M.; Jung, S.; Priller, J. Microglia biology: One century of evolving concepts. Cell 2019, 179, 292–311.
Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308, 1314–1318.
Franze, K. The mechanical control of nervous system development. Development 2013, 140, 3069–3077.
Sweeney, M.D.; Zhao, Z.; Montagne, A.; Nelson, A.R.; Zlokovic, B.V. Blood-brain barrier: From physiology to disease and back. Physiol. Rev. 2018, 99, 21–78.
Winkler, E.A.; Bell, R.D.; Zlokovic, B.V. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol. Neurodegener. 2010, 5, 32.
Alahmari, A. Blood-Brain Barrier Overview: Structural and Functional Correlation. Neural Plast 2021, 2021, 6564585.
Daneman, R.; Prat, A. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 2015, 7, a020412.
Kadry, H.; Noorani, B.; Cucullo, L. A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 2020, 17, 69.
Kaya, M.; Ahishali, B. Basic physiology of the blood-brain barrier in health and disease: A brief overview. Tissue Barriers 2021, 9, 1840913.
Zenaro, E.; Piacentino, G.; Constantin, G. The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis. 2017, 107, 41–56.
Chow, B.W.; Gu, C. The molecular constituents of the blood–brain barrier. Trends Neurosci. 2015, 38, 598–608.
Yang, A.C.; Stevens, M.Y.; Chen, M.B.; Lee, D.P.; Stähli, D.; Gate, D.; Contrepois, K.; Chen, W.; Iram, T.; Zhang, L.; et al. Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature 2020, 583, 425–430.
Petersen, M.A.; Ryu, J.K.; Akassoglou, K. Fibrinogen in neurological diseases: Mechanisms, imaging and therapeutics. Nat. Rev. Neurosci. 2018, 19, 283–301.
Montagne, A.; Zhao, Z.; Zlokovic, B.V. Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J. Exp. Med. 2017, 214, 3151–3169.
Zlokovic, B.V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci. 2011, 12, 723–738.
Hall, C.N.; Reynell, C.; Gesslein, B.; Hamilton, N.B.; Mishra, A.; Sutherland, B.A.; O’Farrell, F.M.; Buchan, A.M.; Lauritzen, M.; Attwell, D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 2014, 508, 55–60.
Vardy, E.R.; Kellett, K.A.; Cocklin, S.L.; Hooper, N.M. Alkaline phosphatase is increased in both brain and plasma in Alzheimer’s disease. Neurodegener. Dis. 2011, 9, 31–37.
Stahr, N.; Galkina, E.V. Immune Response at the Crossroads of Atherosclerosis and Alzheimer’s Disease. Front. Cardiovasc. Med. 2022, 9, 870144.
Iadecola, C. Atherosclerosis and neurodegeneration: Unexpected conspirators in Alzheimer’s dementia. Arterioscler Thromb Vasc Biol 2003, 23, 1951–1953.
Dolan, H.; Crain, B.; Troncoso, J.; Resnick, S.M.; Zonderman, A.B.; Obrien, R.J. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort. Ann. Neurol. 2010, 68, 231–240.
Kivipelto, M.; Mangialasche, F.; Ngandu, T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat. Rev. Neurol. 2018, 14, 653–666.
de Bruijn, R.F.; Ikram, M.A. Cardiovascular risk factors and future risk of Alzheimer’s disease. BMC Med. 2014, 12, 130.
Biessels, G.J.; Despa, F. Cognitive decline and dementia in diabetes mellitus: Mechanisms and clinical implications. Nat. Rev. Endocrinol. 2018, 14, 591–604.
van Sloten, T.T.; Sedaghat, S.; Carnethon, M.R.; Launer, L.J.; Stehouwer, C.D. Cerebral microvascular complications of type 2 diabetes: Stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol. 2020, 8, 325–336.
Rhea, E.M.; Salameh, T.S.; Logsdon, A.F.; Hanson, A.J.; Erickson, M.A.; Banks, W.A. Blood-brain barriers in obesity. AAPS J. 2017, 19, 921–930.
Xie, L.; Kang, H.; Xu, Q.; Chen, M.J.; Liao, Y.; Thiyagarajan, M.; O’Donnell, J.; Christensen, D.J.; Nicholson, C.; Iliff, J.J. Sleep drives metabolite clearance from the adult brain. Science 2013, 342, 373–377.
Jiang, X.; Andjelkovic, A.V.; Zhu, L.; Yang, T.; Bennett, M.V.L.; Chen, J.; Keep, R.F.; Shi, Y. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog. Neurobiol. 2018, 163–164, 144–171.
Santiago, J.A.; Potashkin, J.A. The Impact of Disease Comorbidities in Alzheimer’s Disease. Front. Aging Neurosci. 2021, 13, 631770.
Rosenberg, G.A. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 2009, 8, 205–216.
Candelario-Jalil, E.; Thompson, J.; Taheri, S.; Grossetete, M.; Adair, J.C.; Edmonds, E.; Prestopnik, J.; Wills, J.; Rosenberg, G.A. Matrix metalloproteinases are associated with increased blood–brain barrier opening in vascular cognitive impairment. Stroke 2011, 42, 1345–1350.
Huang, Y.; Mahley, R.W. Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol. Dis. 2014, 72, 3–12.
Zhao, N.; Liu, C.-C.; Qiao, W.; Bu, G. Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol. Psychiatry 2018, 83, 347–357.
Alagarsamy, J.; Jaeschke, A.; Hui, D.Y. Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases. Int. J. Mol. Sci. 2022, 23, 9892.
Vecchio, F.L.; Bisceglia, P.; Imbimbo, B.P.; Lozupone, M.; Latino, R.R.; Resta, E.; Leone, M.; Solfrizzi, V.; Greco, A.; Daniele, A. Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease? Ther. Adv. Chronic Dis. 2022, 13, 20406223221081605.
Fernández-Calle, R.; Konings, S.C.; Frontiñán-Rubio, J.; García-Revilla, J.; Camprubí-Ferrer, L.; Svensson, M.; Martinson, I.; Boza-Serrano, A.; Venero, J.L.; Nielsen, H.M. APOE in the bullseye of neurodegenerative diseases: Impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases. Mol. Neurodegener. 2022, 17, 62.
Liu, C.-C.; Zhao, J.; Fu, Y.; Inoue, Y.; Ren, Y.; Chen, Y.; Doss, S.V.; Shue, F.; Jeevaratnam, S.; Bastea, L. Peripheral apoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function. Nat. Neurosci. 2022, 25, 1020–1033.
Jackson, R.J.; Meltzer, J.C.; Nguyen, H.; Commins, C.; Bennett, R.E.; Hudry, E.; Hyman, B.T. APOE4 derived from astrocytes leads to blood-brain barrier impairment. Brain 2022, 145, 3582–3593.
Greene, C.; Campbell, M. Tight junction modulation of the blood brain barrier: CNS delivery of small molecules. Tissue Barriers 2016, 4, e1138017.
González-Mariscal, L.; Betanzos, A.; Nava, P.; Jaramillo, B.E. Tight junction proteins. Prog. Biophys. Mol. Biol. 2003, 81, 1–44.
Cabral-Pacheco, G.A.; Garza-Veloz, I.; Castruita-De la Rosa, C.; Ramirez-Acuña, J.M.; Perez-Romero, B.A.; Guerrero-Rodriguez, J.F.; Martinez-Avila, N.; Martinez-Fierro, M.L. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int. J. Mol. Sci. 2020, 21, 9739.
Rempe, R.G.; Hartz, A.M.S.; Bauer, B. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers. J. Cereb. Blood Flow Metab. 2016, 36, 1481–1507.
Ayka, A.; Şehirli, A. The Role of the SLC Transporters Protein in the Neurodegenerative Disorders. Clin. Psychopharmacol. Neurosci. Off. Sci. J. Korean Coll. Neuropsychopharmacol. 2020, 18, 174–187.
Gil-Martins, E.; Barbosa, D.J.; Silva, V.; Remião, F.; Silva, R. Dysfunction of ABC transporters at the blood-brain barrier: Role in neurological disorders. Pharmacol. Ther. 2020, 213, 107554.
Uchida, Y.; Ohtsuki, S.; Katsukura, Y.; Ikeda, C.; Suzuki, T.; Kamiie, J.; Terasaki, T. Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptors. J. Neurochem. 2011, 117, 333–345.
Banks, W.A. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009, 9, S3.
Al-Majdoub, Z.M.; Al Feteisi, H.; Achour, B.; Warwood, S.; Neuhoff, S.; Rostami-Hodjegan, A.; Barber, J. Proteomic Quantification of Human Blood–Brain Barrier SLC and ABC Transporters in Healthy Individuals and Dementia Patients. Mol. Pharm. 2019, 16, 1220–1233.
Kook, S.-Y.; Hong, H.S.; Moon, M.; Ha, C.M.; Chang, S.; Mook-Jung, I. Aβ1–42-RAGE Interaction Disrupts Tight Junctions of the Blood–Brain Barrier Via Ca2+-Calcineurin Signaling. J. Neurosci. 2012, 32, 8845–8854.
Yamazaki, Y.; Shinohara, M.; Shinohara, M.; Yamazaki, A.; Murray, M.E.; Liesinger, A.M.; Heckman, M.G.; Lesser, E.R.; Parisi, J.E.; Petersen, R.C.; et al. Selective loss of cortical endothelial tight junction proteins during Alzheimer’s disease progression. Brain J. Neurol. 2019, 142, 1077–1092.
Knox, E.G.; Aburto, M.R.; Clarke, G.; Cryan, J.F.; O’Driscoll, C.M. The blood-brain barrier in aging and neurodegeneration. Mol. Psychiatry 2022, 27, 2659–2673.
Zhou, R.; Chen, L.L.; Yang, H.; Li, L.; Liu, J.; Chen, L.; Hong, W.J.; Wang, C.G.; Ma, J.J.; Huang, J.; et al. Effect of High Cholesterol Regulation of LRP1 and RAGE on Aβ Transport Across the Blood-Brain Barrier in Alzheimer’s Disease. Curr. Alzheimer Res. 2021, 18, 428–442.
Boado, R.J. Molecular regulation of the blood-brain barrier GLUT1 glucose transporter by brain-derived factors. In Ageing and Dementia; Springer: Vienna, Austria, 1998; pp. 323–331.
Chen, Y.; Joo, J.; Chu, J.M.; Chang, R.C.; Wong, G.T. Downregulation of the glucose transporter GLUT 1 in the cerebral microvasculature contributes to postoperative neurocognitive disorders in aged mice. J. Neuroinflammation 2023, 20, 237.
Deane, R.; Sagare, A.; Zlokovic, B.V. The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer’s disease. Curr. Pharm. Des. 2008, 14, 1601–1605.
Boucher, P.; Herz, J. Signaling through LRP1: Protection from atherosclerosis and beyond. Biochem. Pharmacol. 2011, 81, 1–5.
Storck, S.E.; Kurtyka, M.; Pietrzik, C.U. Brain endothelial LRP1 maintains blood–brain barrier integrity. Fluids Barriers CNS 2021, 18, 27.
Sita, G.; Graziosi, A.; Hrelia, P.; Morroni, F. NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration. Int. J. Mol. Sci. 2021, 22, 6984.
Merlini, M.; Rafalski, V.A.; Rios Coronado, P.E.; Gill, T.M.; Ellisman, M.; Muthukumar, G.; Subramanian, K.S.; Ryu, J.K.; Syme, C.A.; Davalos, D.; et al. Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model. Neuron 2019, 101, 1099–1108.e1096.
Al-Ghraiybah, N.F.; Wang, J.; Alkhalifa, A.E.; Roberts, A.B.; Raj, R.; Yang, E.; Kaddoumi, A. Glial Cell-Mediated Neuroinflammation in Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 10572.
Heithoff, B.P.; George, K.K.; Phares, A.N.; Zuidhoek, I.A.; Munoz-Ballester, C.; Robel, S. Astrocytes are necessary for blood–brain barrier maintenance in the adult mouse brain. Glia 2021, 69, 436–472.
Galea, I. The blood–brain barrier in systemic infection and inflammation. Cell. Mol. Immunol. 2021, 18, 2489–2501.
Liang, T.; Zhang, Y.; Wu, S.; Chen, Q.; Wang, L. The Role of NLRP3 Inflammasome in Alzheimer’s Disease and Potential Therapeutic Targets. Front. Pharmacol. 2022, 13, 845185.
Al Rihani, S.B.; Darakjian, L.I.; Kaddoumi, A. Oleocanthal-Rich Extra-Virgin Olive Oil Restores the Blood-Brain Barrier Function through NLRP3 Inflammasome Inhibition Simultaneously with Autophagy Induction in TgSwDI Mice. ACS Chem. Neurosci. 2019, 10, 3543–3554.
Pizzino, G.; Irrera, N.; Cucinotta, M.; Pallio, G.; Mannino, F.; Arcoraci, V.; Squadrito, F.; Altavilla, D.; Bitto, A. Oxidative Stress: Harms and Benefits for Human Health. Oxid. Med. Cell Longev. 2017, 2017, 8416763.
Wood, C.A.P.; Zhang, J.; Aydin, D.; Xu, Y.; Andreone, B.J.; Langen, U.H.; Dror, R.O.; Gu, C.; Feng, L. Structure and mechanism of blood-brain-barrier lipid transporter MFSD2A. Nature 2021, 596, 444–448.
Song, K.; Li, Y.; Zhang, H.; An, N.; Wei, Y.; Wang, L.; Tian, C.; Yuan, M.; Sun, Y.; Xing, Y.; et al. Oxidative Stress-Mediated Blood-Brain Barrier (BBB) Disruption in Neurological Diseases. Oxidative Med. Cell. Longev. 2020, 2020, 4356386.
Alcendor, D.J. Interactions between Amyloid-Β Proteins and Human Brain Pericytes: Implications for the Pathobiology of Alzheimer’s Disease. J. Clin. Med. 2020, 9, 1490.
Ding, R.; Hase, Y.; Ameen-Ali, K.E.; Ndung’u, M.; Stevenson, W.; Barsby, J.; Gourlay, R.; Akinyemi, T.; Akinyemi, R.; Uemura, M.T.; et al. Loss of capillary pericytes and the blood–brain barrier in white matter in poststroke and vascular dementias and Alzheimer’s disease. Brain Pathol. 2020, 30, 1087–1101.
Nortley, R.; Korte, N.; Izquierdo, P.; Hirunpattarasilp, C.; Mishra, A.; Jaunmuktane, Z.; Kyrargyri, V.; Pfeiffer, T.; Khennouf, L.; Madry, C.; et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 2019, 365, eaav9518.
Blanchard, J.W.; Bula, M.; Davila-Velderrain, J.; Akay, L.A.; Zhu, L.; Frank, A.; Victor, M.B.; Bonner, J.M.; Mathys, H.; Lin, Y.-T.; et al. Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat. Med. 2020, 26, 952–963.
Liu, L.; Wan, W.; Xia, S.; Kalionis, B.; Li, Y. Dysfunctional Wnt/β-catenin signaling contributes to blood–brain barrier breakdown in Alzheimer’s disease. Neurochem. Int. 2014, 75, 19–25.
Wang, Q.; Huang, X.; Su, Y.; Yin, G.; Wang, S.; Yu, B.; Li, H.; Qi, J.; Chen, H.; Zeng, W.; et al. Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease. Brain J. Neurol. 2022, 145, 4474–4488.
Gastfriend, B.D.; Nishihara, H.; Canfield, S.G.; Foreman, K.L.; Engelhardt, B.; Palecek, S.P.; Shusta, E.V. Wnt signaling mediates acquisition of blood–brain barrier properties in naïve endothelium derived from human pluripotent stem cells. eLife 2021, 10, e70992.
Hussain, B.; Fang, C.; Huang, X.; Feng, Z.; Yao, Y.; Wang, Y.; Chang, J. Endothelial β-Catenin Deficiency Causes Blood-Brain Barrier Breakdown via Enhancing the Paracellular and Transcellular Permeability. Front. Mol. Neurosci. 2022, 15, 895429.
Yang, A.C.; Vest, R.T.; Kern, F.; Lee, D.P.; Agam, M.; Maat, C.A.; Losada, P.M.; Chen, M.B.; Schaum, N.; Khoury, N. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 2022, 603, 885–892.
Zhao, Z.; Sagare, A.P.; Ma, Q.; Halliday, M.R.; Kong, P.; Kisler, K.; Winkler, E.A.; Ramanathan, A.; Kanekiyo, T.; Bu, G.; et al. Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat. Neurosci. 2015, 18, 978–987.
Juul Rasmussen, I.; Tybjærg-Hansen, A.; Rasmussen, K.L.; Nordestgaard, B.G.; Frikke-Schmidt, R. Blood-brain barrier transcytosis genes, risk of dementia and stroke: A prospective cohort study of 74,754 individuals. Eur. J. Epidemiol. 2019, 34, 579–590.
O’Driscoll, M.C.; Daly, S.B.; Urquhart, J.E.; Black, G.C.; Pilz, D.T.; Brockmann, K.; McEntagart, M.; Abdel-Salam, G.; Zaki, M.; Wolf, N.I. Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. Am. J. Hum. Genet. 2010, 87, 354–364.
Wyss, L.; Schäfer, J.; Liebner, S.; Mittelbronn, M.; Deutsch, U.; Enzmann, G.; Adams, R.H.; Aurrand-Lions, M.; Plate, K.H.; Imhof, B.A. Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus. PLoS ONE 2012, 7, e45619.
Akawi, N.A.; Canpolat, F.E.; White, S.M.; Quilis-Esquerra, J.; Morales Sanchez, M.; Gamundi, M.J.; Mochida, G.H.; Walsh, C.A.; Ali, B.R.; Al-Gazali, L. Delineation of the clinical, molecular and cellular aspects of novel JAM 3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Hum. Mutat. 2013, 34, 498–505.
Chabriat, H.; Joutel, A.; Dichgans, M.; Tournier-Lasserve, E.; Bousser, M.-G. Cadasil. Lancet Neurol. 2009, 8, 643–653.
Ghosh, M.; Balbi, M.; Hellal, F.; Dichgans, M.; Lindauer, U.; Plesnila, N. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann. Neurol. 2015, 78, 887–900.
Guerreiro, R.; Wojtas, A.; Bras, J.; Carrasquillo, M.; Rogaeva, E.; Majounie, E.; Cruchaga, C.; Sassi, C.; Kauwe, J.S.; Younkin, S. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 2013, 368, 117–127.
Jonsson, T.; Stefansson, H.; Steinberg, S.; Jonsdottir, I.; Jonsson, P.V.; Snaedal, J.; Bjornsson, S.; Huttenlocher, J.; Levey, A.I.; Lah, J.J. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 2013, 368, 107–116.
Winfree, R.L.; Dumitrescu, L.; Blennow, K.; Zetterberg, H.; Gifford, K.A.; Pechman, K.R.; Jefferson, A.L.; Hohman, T.J. Biological correlates of elevated soluble TREM2 in cerebrospinal fluid. Neurobiol. Aging 2022, 118, 88–98.
Wu, R.; Li, X.; Xu, P.; Huang, L.; Cheng, J.; Huang, X.; Jiang, J.; Wu, L.-J.; Tang, Y. TREM2 protects against cerebral ischemia/reperfusion injury. Mol. Brain 2017, 10, 20.
Wang, Q.; Yang, W.; Zhang, J.; Zhao, Y.; Xu, Y. TREM2 overexpression attenuates cognitive deficits in experimental models of vascular dementia. Neural Plast. 2020, 2020.
Taylor, X.; Cisternas, P.; You, Y.; You, Y.; Xiang, S.; Marambio, Y.; Zhang, J.; Vidal, R.; Lasagna-Reeves, C.A. A1 reactive astrocytes and a loss of TREM2 are associated with an early stage of pathology in a mouse model of cerebral amyloid angiopathy. J. Neuroinflam. 2020, 17, 223.
Rauchmann, B.-S.; Sadlon, A.; Perneczky, R.; Initiative, A.s.D.N. Soluble TREM2 and inflammatory proteins in Alzheimer’s disease cerebrospinal fluid. J. Alzheimer’s Dis. 2020, 73, 1615–1626.
Nation, D.A.; Sweeney, M.D.; Montagne, A.; Sagare, A.P.; D’Orazio, L.M.; Pachicano, M.; Sepehrband, F.; Nelson, A.R.; Buennagel, D.P.; Harrington, M.G. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med. 2019, 25, 270–276.
Van Dyck, C.H.; Swanson, C.J.; Aisen, P.; Bateman, R.J.; Chen, C.; Gee, M.; Kanekiyo, M.; Li, D.; Reyderman, L.; Cohen, S. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 2023, 388, 9–21.
Erickson, M.A.; Banks, W.A. Blood–brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J. Cereb. Blood Flow Metab. 2013, 33, 1500–1513.

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