Abstract
Among the LDL receptor (LDLR) family members, the roles of LDLR-related protein (LRP)1 in the pathogenesis of Alzheimer’s disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological, and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years. Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid-β peptides (Aβs) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in Aβ-independent manners. Several preclinical studies have also demonstrated an involvement of LRP1 in regulating the pathogenic role of apoE, whose gene is the strongest genetic risk factor for AD. Nonetheless, evidence from clinical studies is not sufficient to conclude how LRP1 contributes to AD development. Thus, despite very promising results from preclinical studies, the role of LRP1 in AD pathogenesis remains to be further clarified. In this review, we discuss the potential mechanisms underlying how LRP1 affects AD pathogenesis through Aβ-dependent and -independent pathways by reviewing both clinical and preclinical studies. We also discuss potential therapeutic strategies for AD by targeting LRP1.
Keywords: low density lipoprotein receptor-related protein 1, gene expression, receptors/lipoprotein, transport
The LDL receptor (LDLR) family members are cell surface receptors sharing structural and functional similarities, which include LDLR, LDLR-related protein (LRP)1, LRP1B, megalin/LRP2, VLDL receptor (VLDLR), apoE receptor 2 (apoER2), sortilin-related receptor (SorLA/LR11), LRP5, and LRP6. These receptors have distinct physiological or pathophysiolgical roles, likely due to differences in their affinity to ligands, protein stability, endocytosis rate, signaling potency, cellular localization, and tissue expression pattern. While these receptors bind diverse extracellular ligands, some of them recognize key molecules in the pathogenesis of Alzheimer’s disease (AD), such as apoE and amyloid-β peptides (Aβs) for cellular trafficking and/or signaling pathways. Given that the ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for AD among the three human alleles (ε2, ε3, and ε4), the potential contributions of LDLR family members to AD development have attracted great interest by many laboratories around the world for over two decades (1, 2).
Cumulative evidence from preclinical studies using cellular or animal studies indicates that LDLR family members can contribute to AD pathogenesis through modulating Aβ accumulation or neurodegenerative processes. However, as there are currently no complete cellular or animal models that can recapitulate all pathological features of AD, parallel understanding between cellular/animal studies and human studies is necessary to define the specific role of any molecule in AD pathogenesis. Herein, among the LDLR family members, we comprehensively discuss the roles of LRP1 in AD pathogenesis by reviewing both preclinical studies using cellular/animal models, and clinical studies analyzing human samples/cohorts. We will specifically review current knowledge regarding: 1) LRP1 expression during AD progression, 2) contribution of LRP1 to Aβ metabolism, 3) the role of LRP1 in brain homeostasis, and 4) apoE-LRP1 pathways in AD pathogenesis. Finally, we will also discuss potential therapeutic strategies targeting LRP1 to prevent or treat AD.
STRUCTURAL AND FUNCTIONAL FEATURES
LRP1 was first identified in 1988 from mouse lymphocyte and human liver cDNA libraries by screening for homologous sequences of the apoE-binding domain within LDLR (3). LRP1 is a very large type I transmembrane protein compared with LDLR (Fig. 1). It encodes a 4,525 amino acid protein, composed of a large 515 kDa N-terminal extracellular subunit and an 85 kDa C-terminal transmembrane subunit, which are noncovalently associated with one another (4). The two subunits of LRP1 are generated by furin cleavage in the trans-Golgi complex before being transported to the cell surface (4, 5). The extracellular domain has four ligand binding domains (I–IV) with 2, 8, 10, and 11 cysteine-rich complement-type repeats, respectively, where domains II and IV are the major binding regions for almost all ligands in the presence of calcium (6, 7). Most LDLR family members have NPXY motif(s) in their cytoplasmic tails, which serve as a signal for endocytosis through clathrin-coated pits (8). Moreover, LRP1 has a YXXL motif adjacent to the second NPXY motif, enabling rapid endocytosis together with the proximal di-leucine motif (9). Cysteine-rich EGF repeats and a YWTD β-propeller domain in the extracellular portion facilitate dissociation of ligands in the endocytic vesicles (10). The efficient delivery of LRP1 to the cell surface requires receptor-associated protein (RAP), a molecular chaperone of 39 kDa in size (11, 12). RAP associates with LRP1 in the early secretary pathway, thereby preventing premature binding of LRP1 with other ligands. Dissociation from RAP occurs at the lower pH encountered in the late secretory pathway (13). RAP is a unique ligand for LRP1 in terms of universally inhibiting all known ligand interactions with LRP1 (13).
Fig. 1.
Schematic diagram of domain structure for LRP1 and LDLR. The large extracellular domain of LRP1 has four ligand binding domains (I–IV) with 2, 8, 10, and 11 cysteine-rich complement-type repeats, respectively, while that of LDLR has one ligand binding domain with seven such repeats. The extracellular domain of LRP1 is cleaved by furin, and attached with the C-terminal domain via a noncovalent association. Cysteine-rich EGF repeat and YWTD β-propeller domain in the extracellular portion facilitate dissociation of ligands within the endocytic pathway under acidic conditions. In the cytoplasmic tail, in addition to the two NPXY motifs, LRP1 has an YXXL motif adjacent to the second NPXY motif, enabling rapid endocytosis.
Over 40 proteins, including Aβ, apoE, and activated α2-macroglobulin, are reported to be ligands for LRP1 (14). However, it is controversial whether Aβ directly binds to these domains of LRP1; though Deane et al. (15) demonstrated that domains II and IV bind with Aβs (especially monomeric Aβ40) in vitro, such results were not confirmed in a similar assay by Yamada et al. (16). LRP1 might facilitate Aβ uptake into cells through cooperating with other Aβ-binding proteins, such as heparan sulfate proteoglycan (17, 18). Oligomeric or aggregated Aβ is also a poor ligand for LRP1 (15, 19). Of note, the binding of apoE to LRP1 appears to be affected by the conformational and lipidation status of apoE (1).
In addition to controlling ligand metabolism, LRP1 can regulate signaling pathways or functional activations by coupling with other cell surface receptors or proteins, such as the platelet-derived growth factor (20, 21) and the N-methyl-D-aspartate (NMDA) receptor (22, 23). LRP1 can also be cleaved by β-secretase (24, 25) or α-secretase (26) and then γ-secretase (27). The resulting intracellular domain of LRP1 serves as a transcription regulator, affecting expression of several genes, including interferon-γ, similar to amyloid precursor protein (APP) (28–31), while secreted soluble forms of LRP1 (sLRP1) can affect Aβ metabolism (32, 33) as discussed later.
LRP1 is abundantly expressed in diverse tissues, including liver, brain, and vasculatures. Conventional deletion of the LRP1 gene in mice led to early embryonic lethality, which is a remarkable difference when compared with nonlethal LDLR knockout mice (34). Conditional knockouts of LRP1 in hepatocytes, macrophages, adipocytes, or vascular smooth muscle cells in mouse models have supported critical roles of LRP1 in the development and homeostasis of each tissue by regulating the metabolism of ligands, as well as the strength of signaling pathways. Thus, disturbances of LRP1 functions likely contribute to disease development, such as atherosclerosis and cancer, which have been reviewed elsewhere and are beyond the aim of this review (10, 35). As described later, conditional deletion of LRP1 in neurons in mouse models showed several features of neurodegenerative diseases relevant to AD.
CLINICAL EVIDENCE FROM GENETIC, NEUROPATHOLOGICAL, AND BIOMARKER STUDIES
An initial finding from neuropathological studies was the detection of LRP1 and its multiple ligands, including apoE and α2-macroglubulin, on senile plaques in the brains from AD patients, suggesting an involvement of LRP1 in the accumulation of Aβ (36, 37). Following this leading neuropathological finding, several genetic studies have been performed to address the association of LRP1 gene variants with AD risk. Though initial intriguing observations were that a silent polymorphism in the exon 3 at codon 766 (C766T) of LRP1 were under-represented in late-onset AD (38, 39), following results were conflicting (40, 41). A meta-analysis in 2005 combining 4,668 AD patients and 4,473 controls from 18 case-control studies failed to detect a significant effect of the LRP1 C766T polymorphism on AD risk. The obtained results were not affected by AD onset (early- and late-onset) or APOE4 status (42). Also, no significant effects were observed in a recent meta-analysis of four genome-wide association study data sets consisting of 17,008 AD cases and 37,154 controls (43). Nonetheless, another study showed that the effects of the LRP1 C766T polymorphism were especially obvious in the presence of tau intron 9 rs2471738 polymorphism (odds ratio = 6.20, P = 0.005) (44). In addition, by introducing the amyloid imaging 11C-Pittsburgh compound B technique, which enables antemortem detection of Aβ accumulation in the brain through positron emission tomography (45), the LRP1 C667T polymorphism was moderately, but significantly, associated with global amyloid deposition in AD patients (n = 72, P = 0.046) (46). Also, a neuropathological study observed a significant association between the LRP1 C766T polymorphism and cerebral amyloid angiopathy (CAA), where Aβ accumulates around blood vessels, especially in the smooth muscle cell layers; the polymorphism was more frequent in AD patients without capillary CAA, compared with AD cases with capillary CAA and control individuals (47). Other studies showed that not only LRP1 C667T but also LRP1 haplotypes influence the risk for AD or the preclinical stage of AD (48, 49). Together, these genetic studies suggest that influences of LRP1 on AD risk may differ depending on the status of Aβ pathology, CAA formation, and tauopathy, although further studies are needed.
In addition to LRP1 gene polymorphisms, many studies using human postmortem brain samples have focused on understanding how LRP1 levels are modulated during the AD pathogenesis (Table 1). Some groups reported that LRP1 mRNA levels are increased in the temporal cortex and hippocampus of AD patients or demented individuals (50, 51) although there is a conflicting report showing decreased levels of LRP1 mRNA expression in the frontal cortex of AD patients (52). Because LRP1 is expressed in diverse cells, including neurons, astrocytes, and vasculatures in the brain, LRP1 levels may be differently altered depending on cell types in AD (53, 54). Indeed, it was reported that LRP1 levels were decreased in neurons, but increased in vasculatures or astrocytes proximate to amyloid plaques in AD brains (53–55). Kang et al. (56) demonstrated that LRP1 levels in the frontal cortex were lower in AD patients compared with age-matched controls when analyzed by Western blotting. An age-dependent reduction of LRP1 was also detected in normal individuals in the same study. Further, they reported an increased LRP1 level in LRP1 C667T carriers (56). However, Qiu et al. (57) observed increased levels of LRP1 in the frontal cortical area, though they used a relatively small number of subjects and antibodies detecting the extracellular domain of LRP1 rather than its C-terminal domain used in the former study. Also, Causevic et al. (58) did not observe an association between LRP1 levels and either dementia status or LRP1 C766T polymorphism, despite examining similar brain areas in a similar number of subjects. On the other hand, our recent studies using ELISA measurements found a significant reduction of LRP1 levels (C-terminal domain) in several cortical areas of AD patients, which were positively correlated with synaptic proteins, including the scaffold protein, postsynaptic density protein 95, at the postsynaptic sites (59). Thus, there is a possibility that the reduction of LRP1 levels in AD brains is caused by neuronal loss as the disease progresses, because neuronal LRP1 accounts for more than 50% of its protein amount in the brain (60). It is of note that oxidized LRP1 was increased in the hippocampus of AD patients, suggesting that posttranslational modifications need to be considered to address the functional change of LRP1 in AD (61).
TABLE 1.
Findings of LRP1 protein or mRNA change from studies analyzing clinical samples related to AD
Study | Objects | Methods | Cohorts | Number of Subjects | Observations | Notes |
Rebeck et al. (36) | LRP1 protein in the temporal cortex (BA20) | Immunohistochemistry | Control and AD patients | n = 35–39/group | Immunoreactivity of N-terminal domain of LRP1 mostly existed in neurons in controls, while astrocytes and senile plaques were also stained in AD. No effects of APOE isoforms | Fixed in paraformaldehyde-lysine-periodate. Cryosection. Mouse monoclonal 8G1 Ab (179) |
Thal, Schober, and Birkenmeier (180) | LRP1 protein in the hippocampus and posterior cortex (BA17) | Immunohistochemistry | Control and AD patients | n = 7–16/group | Immunoreactivity of N-terminal extracellular domain of LRP1 existed in reactive astrocytes surrounding core plaques in AD and some neurons, while that of C-terminal transmembrane domain existed in core plaques | Mouse monoclonal Ab against N-terminal extracellular domain of LRP1 (IIF6), and C-terminal domain of LRP1 (II4/8). Formalin fixed. Paraffin section |
Kang et al. (56) | LRP1 protein levels in the midfrontal cortex | Western blot | Control and AD patients | n = 39/group | LRP1 protein levels were decreased at old age, and further decreased in AD patients. C667T polymorphism was associated with the lower levels of LRP1 | Normalized by actin or synaptophysin. Polyclonal Ab against C-terminal domain of LRP1 (181) |
Shibata et al. (78) | LRP1 protein in the frontal cortex (BA10) | Immunohistochemistry | Control and AD patients | n = 3/group | Decreased immunoreactivity of LRP1 in brain vasculature | R777 Ab for extracellular domain of LRP1 (182). Formalin fixed section or frozen section. No quantification of the data |
Qiu et al. (57) | LRP1 protein levels in the frontal cortex, and sLRP1 levels in CSF | Western blot | Control, other CNS disease, and AD patients | n = 7–9/group (brain), and n = 9–16/group (CSF) | Increased LRP1 protein levels in brain, and sLRP1 levels in CSF of AD patients, compared with controls, and other CNS diseases | R777 Ab for extracellular domain of LRP1. Normalized by total protein levels |
Arélin et al. (55) | LRP1 protein in the brain (area not described) | Immunohistochemistry | Controls and AD patients | n = 3–5/group | LRP1 immunoreactivity was only present in cored plaques among plaques. LRP1 immunoreactivity existed in neurons and reactive astrocytes around plaques | Ab for extracellular domain of LRP1 (182), and C-terminal domain of LRP1 (179). Fixed in paraformaldehyde-lysine-periodate. Cryosection |
Causevic et al. (58) | LRP1 protein levels in the frontal cortex (BA 8/9) | Western blot | Control and AD patients | n = 20–38/group | LRP1 protein levels were not different between controls and AD. LRP1 levels were not associated with cognitive scores, and C667T polymorphism | 1,704 Ab for C-terminal domain of LRP1 (183). Normalized by GAPDH levels |
Donahue et al. (54) | LRP1 protein levels in the hippocampus | Immunohistochemistry and Western blot | Control and AD patients | n = 6/group | LRP1 protein levels in microvasculature were increased in AD, but LRP1 protein levels in neurons were decreased in AD | Rabbit polyclonal antibody (Orbigen Inc.). Normalized by total protein levels. Paraformaldehyde fixed. Cryosection |
Matsui et al. (50) | LRP1 mRNA levels in the temporal cortex | RT-qPCR | Control and AD patients | n = 21–27/group | LRP1 mRNA levels were increased in AD | |
Sultana, Banks, and Butterfield (63) | LRP1 protein levels in the hippocampus | Western blot | Control and MCI | n = 6/group | LRP1 protein levels were decreased in MCI | Ab from Santa Cruz Biotechnology. Normalized by total protein levels |
Owen et al. (61) | LRP1 and oxidized LRP1 in the hippocampus | Western blot and immunoprecipitation | Control and AD patients | n = 9/group | Increased levels of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) bound to LRP1 in AD | Rabbit anti-LRP1 Ab (30) |
Sagare et al. (65) | Oxidized sLRP1 in the plasma | ELISA and enzymatic assay | Control, MCI-AD converters, AD patients | n = 14/group | Oxidized sLRP1 levels were increased in MCI-AD and AD, and its increase correlated with CSF tau/Aβ42 ratio and MMSE reduction | ELISA (coating: recombinant RAP, detection: 8G1 Ab) |
Akram et al. (51) | LRP1 mRNA levels in the inferior temporal cortex and hippocampus | RT-qPCR | Subjects with different CDR and AD pathology | n = 88 (temporal cortex) and 73 (hippocampus) | LRP1 mRNA levels were associated with CDR, Aβ, and tau pathology | Only samples with RIN > 5.5 were included |
Ruzali, Kehoe, and Love (53) | LRP1 mRNA and protein levels | RT-qPCR (mRNA) and dot blot (protein) | Controls and AD patients | n = 19–23/group | LRP1 mRNA levels were increased in meningeal vessels, but not cortex or choroid plexus, in AD and in association with APOE ε4 | Mouse anti-LRP1 Ab (ab28320, Abcam) |
Shinohara and colleagues (59, 117) | LRP1 protein levels in 12 brain areas | ELISA | Control, pathological aging, sporadic AD, and familial AD | n = 10–19/group | Cortical LRP1 protein levels were decreased in AD patients, and the regional distribution of LRP1 in nondemented controls was associated with that of Aβ accumulation | ELISA (coating: 6F8 antibody, detection: 5A6 antibody) Normalized by total protein levels |
Provias and Jeynes (184) | LRP1 protein in the capillary vessels of temporal cortex | Immunohistochemistry | Control and AD patients | n = 15/group | LRP1 positive capillaries were not different between controls and AD, but positively associated with plaque burden in AD | Mouse monoclonal Ab (Biodesign International, ME). No description how to fix the tissue. Paraffin section |
Yamanaka et al. (52) | LRP1 mRNA levels in the superior frontal cortex | RT-qPCR | Controls and AD patients | n = 8–15/group | LRP1 mRNA levels were decreased in AD | No detail description of the procedure, and samples |
BA, Brodmann area; CDR, clinical dementia rating; MMSE, mini-mental state examination.
Importantly, it remains to be clarified whether LRP1 levels change in the preclinical stage of AD. As Aβ accumulation almost reaches a plateau at the preclinical stage of AD (62), functional changes of LRP1 during the early stage of AD might be more relevant to brain Aβ accumulation. In this regard, Sultana, Banks, and Butterfield (63) analyzed postmortem brains from subjects with mild cognitive impairment (MCI), which would correspond to the early stage of AD, and observed a significant decrease of LRP1 levels in the hippocampus of MCI subjects compared with controls. Controversially, compared with normal aging, we failed to see a significant change in LRP1 levels in the cortical areas of pathological aging, which is neuropathologically characterized by the moderate to marked Aβ deposition in nondemented elderly people and, thus, often referred to be comparable to the early stage of AD (64), although we did observe a trend toward increased LRP1 levels in them (59). An interesting finding was made by Sagare et al. (65). They measured the sLRP1 in plasma of MCI individuals who converted to AD later (65). They previously reported that sLRP1 can accelerate Aβ clearance through peripheral “sink” activity, which will be described in the next section (32, 66). In their study, they observed an increase in the plasma of MCI individuals of oxidized sLRP1, which showed extremely low affinity for Aβ, suggesting that Aβ clearance from the brain through peripheral sink activity of sLRP1 is impaired at the early stage of AD (65). Despite these findings, most of the studies employed small cohort size, thus it remains to be clarified whether LRP1 levels and functions are changed prior to AD onset. Additional studies in larger cohorts are warranted to determine whether the quantitative and qualitative changes of LRP1 and its derivatives are causative phenotypes for AD.
LRP1 AND Aβ METABOLISM: PRECLINICAL EVIDENCE FROM CELLULAR AND ANIMAL STUDIES
As Aβ deposition plays a central role in initiating the pathogenesis of AD, it is important to explore how LRP1 is involved in Aβ metabolism. Accordingly, many interesting observations have been reported using cellular or animal models where LRP1 amount or function was biologically or genetically manipulated.
Initial efforts were devoted to addressing the effects of LRP1 on APP trafficking and processing to Aβ by using cellular models, as it was known that LRP1 catabolizes tissue factor pathway inhibitor, and this protein shares the Kunitz protease inhibitor domain with the longer forms of APP (67–70). Blocking LRP1 function by RAP increased cell surface APP and reduced Aβ production in H4 cells stably expressing human APP (69). Consistently, overexpressing a mini-receptor form of LRP1 containing the ligand-binding domain IV reduced cell surface APP in Chinese hamster ovary cells (71). However, other studies showed that overexpression of the LRP1 C-terminal transmembrane domain can reduce Aβ production by competing with APP for processing through β-secretase and γ-secretase in neuronal cell lines (24, 27). These conflicting results might be due to differences in experimental conditions, such as cell types, expression status of LRP1 or APP, or ways that LRP1 function was manipulated. Nonetheless, these results imply that LRP1 has the ability to modulate APP processing and subsequent Aβ generation.
LRP1 is a fast endocytic receptor mediating the trafficking and lysosomal degradation of an array of ligands. By focusing on such a function of LRP1, it has also been intensely studied regarding how LRP1 modulates the cellular uptake, trafficking, degradation and/or aggregation of Aβ. An initial finding was that activated α2-macroglobulin, an LRP1 ligand, strongly binds Aβ and promotes Aβ uptake into the glioblastoma cells or cortical neurons, which was blocked by RAP (72, 73). Our recent study using cellular-specific LRP1 knockout mice in the background of APP/PS1, which overexpress a mutant form of APP (KM670/671NL) and presenilin-1 (ΔE9) (74), demonstrated the receptor-mediated clearance of Aβ through LRP1 in neurons and astrocytes (75, 76). Aside from the brain parenchymal cells, vascular cells were also reported to internalize Aβ through LRP1 (77). By injecting [125I]Aβ40 into rodents, several interesting observations regarding the role of vascular LRP1 in Aβ metabolism were reported. One group showed the existence of an active transport system of Aβ from brain to plasma at the blood-brain barrier (BBB), which was blocked by LRP1 ligands and anti-LRP1 antibody (15, 78), while another group failed to show the existence of such a system at the BBB (79). Although it has been debated whether internalized Aβ in the endothelial cells would move into the lysosome for degradation, or to the other side of cells for transcytosis (16, 79–82), several other groups have also reported LRP1-mediated Aβ clearance in animal models (83, 84). In particular, a recent animal model study nicely demonstrated the existence of the LRP1-mediated Aβ transport system at the BBB using a conditional mouse model deleting LRP1 in endothelial cells (84). MEOX2 homeobox gene controls LRP1 expression at the BBB, and might link to neurovascular dysfunction in AD (85), while another group reported that haploinsufficiency of the MEOX2 gene did not affect plaque deposition in APP/PS1 mice (86). Of note, the choroid plexus, which forms the blood-cerebrospinal fluid (CSF) barrier, can actively eliminate Aβ from CSF through LRP1, forming a critical pathway regulating Aβ levels in CSF (87). The important roles of LRP1 in vascular mural cells (vascular smooth muscle cells and pericytes) were also reported. Serum response factor and myocardin regulate LRP1 expression in smooth muscle cells and control cerebrovascular clearance of Aβ (88). Our group also has demonstrated that conditional deletion of LRP1 in vascular smooth muscle cells increases Aβ deposition as plaques and CAA in APP/PS1 model (89). Pericytes, which regulate several neurovascular functions, including BBB integrity and cerebral blood flow, can clear Aβ through LRP1, and loss of pericytes exaggerated Aβ accumulation in Tg2576 mice, which overexpress a mutant form of APP (KM670/671NL) under the hamster prion promoter (90, 91). LRP1 in vascular mural cells might promote lysosomal degradation of Aβ or control the perivascular drainage pathway of Aβ (92).
It is noteworthy that LRP1 in peripheral tissues could influence Aβ metabolism in the brain. It has been hypothesized that a dynamic equilibrium exists between Aβ pools in the periphery and those in the brain (peripheral sink hypothesis) (66, 93, 94). Large portions of Aβ in plasma is cleared through the liver (95, 96), and LRP1 is a major receptor for Aβ in the liver (97). Thus, upregulating LRP1 in the liver could accelerate the elimination of peripherally circulating Aβ, allowing brain Aβ sinks into the blood through the BBB. Consistently, modulating LRP1 function in the liver through pharmacological or nonpharmacological approaches was associated with reduced Aβ accumulation in mouse brain (98, 99). In addition, circulating sLRP1 in plasma may also help Aβ clearance to reduce Aβ accumulation in the brains of Tg2576 mice, which would be consistent with the peripheral sink hypothesis (32, 65). However, such a hypothesis has been questioned by several studies, including recent ones showing that reduction of plasma Aβ by neprilysin, an Aβ degrading enzyme (100), did not affect brain Aβ levels in mice and monkeys (101–103). Also, the function of sLRP1 remains to be further clarified; whether it binds directly with Aβ (16, 17) and whether it interferes with the normal function of LRP1. The latter point might be more important in a subset of AD patients whose BBB integrity is disturbed (104) and, thus, circulating sLRP1 might enter the brain. Cumulatively, LRP1 expressed in neurons (17, 73, 75), astrocytes (19, 76, 105), microglia (106), endothelial cells (16, 78, 84), vascular smooth muscle cells or pericytes (88–90, 107), choroid plexus (87, 108), plasma (32), and liver (97–99) was reported to be involved in Aβ cellular uptake and/or clearance (Fig. 2). Further studies would be warranted to address the relative contributions of LRP1 in different cell types and tissues to brain Aβ metabolism. Additional aspects regarding LRP1-mediated Aβ clearance systems and their potential mechanism have been discussed in detail in our previous review (2, 109).
Fig. 2.
Proposed LRP1-related pathways for Aβ production, clearance, and accumulation and their relationship with apoE. Aβ production from APP in neurons might be influenced by LRP1 through its interaction with APP or competition with the β/γ-secretase cleavage of APP. Once Aβ is produced and secreted into the extracellular space in the brain, LRP1 is involved in cellular uptake of Aβ in neurons, microglia, astrocytes, vascular smooth muscle cells, pericytes, endothelial cells, and the choroid plexus. It might be context-dependent whether internalized Aβ is degraded in lysosomes or accumulated in the cells provoking cellular toxicity. A portion of Aβ may be transported through LRP1 at the BBB or pulled out by sink activity of soluble LRP1 into the blood. LRP1 in the liver might also help clear Aβ from the blood, possibly leading to the elimination of Aβ from the brain. apoE, which is mainly produced and secreted from astrocytes in the brain, is lipidated by ABCA1 to supply cholesterol/lipids to neurons and other cells through LRP1. apoE isoforms likely affect LRP1-mediated Aβ metabolism by directly interacting with Aβ or competing with Aβ for receptor binding.
Importantly, it remains to be further clarified whether Aβ metabolism mediated by LRP1 would benefit Aβ clearance or exacerbate Aβ accumulation during AD pathogenesis. Indeed, although complete neuronal deletion of LRP1 exaggerates Aβ accumulation (75), we also observed that functional enhancement of the LRP1 mini-receptor, mLRP2, in neurons increased soluble Aβ and intraneuronal Aβ accumulation in PDAPP mouse models (110, 111). As lysosomal function can be perturbed by the excess amount of aggregated Aβ and aging-related stress, which manifests in AD (112, 113), the LRP1-mediated Aβ uptake pathway could lead to either clearance or accumulation of Aβ. Indeed, mice deficient of vitamin E synthesis enzyme showed increased levels of LRP1 in brain vasculature, but impaired Aβ clearance from the brain, although they also exhibited decreased levels of insulin-degrading enzyme, an Aβ degrading enzyme (98, 114). Of note, although LRP1 can protect against Aβ toxicity (115), internalized Aβ through LRP1 also could provoke cellular toxicity and lethality, which might promote the neurodegenerative pathway in AD (107, 116). In addition to the trend of increased LRP1 levels in the presumable early stage of AD, as mentioned before, we observed significant regional associations between Aβ, synaptic markers, and LRP1 in nondemented individuals and sporadic AD patients, which would provide important insights into the pathogenesis of Aβ accumulation (59, 117). Taken together, these results suggest that LRP1 could play a role in promoting Aβ accumulation and its toxicity in AD pathogenesis. Further studies are needed to define whether LRP1 helps Aβ clearance or exacerbates Aβ accumulation during AD pathogenesis.
LRP1 AND Aβ-INDEPENDENT PATHWAYS IN AD PATHOGENESIS
LRP1, which is distributed in the post synapses of neurons, interacts directly or indirectly with several synaptic proteins, including postsynaptic density protein 95 (22), NMDA receptor subunit, NMDAR1 (118) and NMDAR2A (22, 23), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit, GluA1 (119, 120), thereby regulating their trafficking, turnover, and functions. Of note, LRP1 was also shown to regulate insulin signaling and glucose uptake in mouse brains by coupling with the insulin receptor β and reducing the levels of glucose transporters, GLUT3 and GLUT4, in neurons (121). Moreover, LRP1 interacts with leptin/leptin receptor complex in the hypothalamus to regulate its signaling pathway. Deletion of neuronal LRP1 resulted in increased food intake and decreased energy consumption causing obesity and diabetic phenotypes (60). Thus, the deletion of LRP1 in neurons has been shown to affect multiple pathways not directly related to Aβ metabolism: NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazole propionate signaling, lipid metabolism, leptin signaling, glucose metabolism, insulin signaling, and anti-apoptotic signaling that lead to neuroinflammation, motor dysfunction, and cognitive function in mice (22, 60, 118, 119, 121, 122).
These findings clearly indicate that LRP1 plays very important roles in neuronal function, and its perturbation contributes to neurodegeneration. Some of these features indeed might be a trigger for AD pathogenesis. For example, the reduction of sulfatide levels by LRP1 deletion (118) was observed in the brains of early stage of AD cases (123). Dysfunction of NMDA neurotransmission might contribute to the pathogenesis of AD (124). Increasing evidence demonstrates that diabetes is associated with increased risk for AD through Aβ-dependent and independent mechanisms; impaired insulin/insulin-like growth factors signaling and a compromised glucose-energy balance in the brain are predicted to impact cognitive performance during aging and AD (125). Given that hyperglycemia decreases brain LRP levels (121), it is possible that neuronal LRP1 plays a role in diabetes-related AD pathogenesis. Leptin signaling, which is regulated by LRP1, might also contribute to AD pathogenesis (126).
However, because LRP1 deletion also leads to phenotypes uncommon to AD, it remains to be further clarified whether reduction of LRP1 levels in AD brains could be interpreted as a driving event or a downstream event in the neurodegenerative processes. Also, few studies exist addressing the effects of LRP1 on tau accumulation, which is another important pathological feature of AD (127). Thus, in future animal studies, it should be further clarified whether manipulation of LRP1 expression and function in specific cell types, such as neurons, glia cells, or vascular cells, could lead to cognitive dysfunction, and whether those effects could be reminiscent of neurodegenerative processes of AD, including tau accumulation. Age- or disease stage-specific manipulation would also be helpful to understand the role of LRP1 in AD development and progression.
LRP1 AND apoE IN AD PATHOGENESIS
As APOE4 is the strongest genetic risk factor for AD and apoE is a ligand for LRP1, there is an urgent need to define how apoE mediates AD pathogenesis, and whether LRP1 is involved in apoE-mediated AD pathogenesis (128, 129). Results from genetic studies are conflicting, making it difficult to conclude whether APOE and LRP1 interact with AD risk from the perspective of genetics. Although apoE promotes Aβ accumulation in an apoE-isoform-dependent manner (E4 > E3 > E2) (109), recent clinical and preclinical studies, including ours, demonstrated that apoE isoform also influences cognitive performance and AD development in an Aβ-independent manner (129–133). Thus, in this section, we discuss both Aβ-dependent and Aβ-independent effects of apoE isoform on AD pathogenesis with a specific focus on LRP1-related pathways (Fig. 2).
In vitro experiments have shown that apoE3 produced by human embryonic kidney 293 cells forms apoE3-Aβ complex more than apoE4, and protects against Aβ toxicity in primary neurons, which was blocked by the LRP1 antagonist, RAP (134). While treatments with conditioned medium from apoE2- and apoE3-expressing cells, but not apoE4-expressing cells, facilitated Aβ uptake into Chinese hamster ovary cells, the effects were diminished by anti-LRP1 antibody, suggesting that apoE2 and apoE3, but not apoE4, promote Aβ clearance from the extracellular space through LRP1 (135). Consistently, other studies also revealed that the apoE-LRP1 pathway mediates the synaptic uptake and astrocytic degradation of Aβ (136, 137). When the Aβ-apoE complex was injected into mouse brains, apoE2- and apoE3-bound Aβ was cleared through both LRP1 and VLDLR at the BBB. Interestingly, the rapid clearance of free Aβ from LRP1 is likely redirected to the slower clearance through VLDLR when Aβ is bound to apoE4 (138), although another group observed the apoE isoform-independent effects on the inhibition of Aβ clearance (139). Controversially, several other observations reported that LRP1 rather potentiates apoE-mediated Aβ accumulation (140–142). Whereas these studies generally showed the importance of LRP1 in mediating the metabolism of the apoE-Aβ complex, there is also a report showing that apoE competes with Aβ for interaction with LRP1, resulting in suppressed Aβ clearance (105). These discrepancies might be caused by potentially different properties of Aβ and apoE isoforms (e.g., amount, aggregation, and lipidation status), and different brain areas where Aβ, apoE, and LRP1 interact during the progression of Aβ deposition in AD. In addition to Aβ clearance, LRP1 likely modifies apoE-induced APP processing under certain conditions; the treatment with lipid-poor apoE4 increases Aβ production compared with apoE3 in neuronal cells depending on LRP1 (143).
Regarding the Aβ-independent pathways, an initial study showed that apoE3 purified from human plasma and CSF or reconstituted apoE3 particles, but not apoE4, increases neurite extension in neuronal cells, and this effect was blocked by LRP1 antagonist, RAP, or anti-LRP1 antibody (144–146). A similar phenomenon was also observed using human recombinant apoE; neurite outgrowth was promoted in the presence of apoE3 through LRP1, but suppressed by apoE4, in cultured mouse cortical neurons (147). While astrocytes were shown to promote synaptogenesis, cholesterol carried by apoE-containing lipoprotein particles appears to be essential (148, 149). Of note, the beneficial effect was inhibited in the presence of RAP (148, 149). Consistently, the treatment with a retinoid X receptor agonist, bexarotene, which stimulates apoE production and its lipidation, significantly increased synaptic proteins through neuronal LRP1 in aged mice (150). Furthermore, mouse apoE and human apoE3, but not apoE4, also contribute to several signaling pathways through LRP1 in neurons, including activation of p44/42 MAPK (151), protein kinase C (PKC)δ (152), and PKCε (153), and inactivation of glycogen synthase kinase 3β (GSK3β) (152). Thus, the supplies of cholesterol/lipids to neurons through the apoE-LRP1 pathway and/or subsequent regulation of specific signaling pathways might be critical in maintaining neuronal homeostasis, which likely depends on apoE isoforms. Because apoE4 induces nuclear import of histone deacetylases through LRP1 in neuronal cells resulting in reduced brain-derived neurotrophic factor expression (154), the apoE4-LRP1 axis might facilitate apoE4-related toxic effects.
In addition to neurons, the apoE-LRP1 pathway plays a critical role in BBB integrity. LRP1 is abundantly expressed in pericytes at the BBB, where apoE prevents the activation of the proinflammatory cyclophilin A-nuclear factor κ-light-chain-enhancer of activated B cells-matrix metallopeptidase 9 (CypA-NFκB-MMP9) pathway through LRP1 (155). A study using an in vitro BBB model also showed that apoE3 induces PKCη activation and phosphorylation of a tight junction protein, occludin, in endothelial cells to preserve BBB integrity, which was blocked by RAP and anti-LRP1 antibody (156). However, both reports demonstrated that those protective effects are deficient in apoE4, which is potentially associated with BBB dysfunction (155, 156). apoE3 also inhibits pericyte mobility through LRP1, while apoE4 does not have such effects (157).
Though these studies showed Aβ-independent effects of apoE on synaptic degeneration or vascular dysfunction through LRP1, it remains to be clarified whether and how these effects contribute to AD pathogenesis. Indeed, we recently observed that apoE2 protects against cognitive decline during aging, while apoE4 exaggerates it independent of amyloid accumulation. Of note, in our animal study, these effects also appeared to be independent of synaptic degeneration and neuroinflammation (133). Thus, future efforts should be devoted to clinical studies addressing the importance of these Aβ-independent effects of apoE through LRP1 during AD pathogenesis or cognitive decline during aging.
LRP1 AS A THERAPEUTIC TARGET FOR AD
Several pharmaceutical and nonpharmaceutical methods were reported to modulate LRP1 function and benefit AD-related pathogenesis in animal models (Fig. 3). Although some of them have multiple targets in addition to LRP1, their translation into clinical trials could provide opportunities to understand how LRP1 is involved in AD pathogenesis in humans.
Fig. 3.
Potential therapeutics for AD targeting LRP1. Several pharmacological approaches [cyan colored: statins, Withania somnifera, oleocanthal, cannabinoid, intravenous immunoglobulin (IVIG), and α-secretase inhibitors] and several nonpharmacological approaches (green colored: environmental enrichment, electroacupuncture, and exercise) might be promising therapeutic strategies for AD by enhancing LRP1-mediated Aβ clearance pathways. The treatment with LRPIV-D3674G mimicking soluble LRP1 may also facilitate Aβ elimination from brain through sink activity. Because the role of LRP1 in AD pathogenesis is likely context-dependent, further preclinical studies are desired to define the potential impacts of LRP1-targeted therapy on AD-related phenotypes prior to moving to clinical trials.
Environmental enrichment conditions could ameliorate cognitive function and amyloid pathology in amyloid AD mouse models (158, 159). The receptor for advanced glycation end products was reported to mediate Aβ influx into the brain across the BBB (160). In TgCRND8 mice, which overexpress a double mutant form of APP (KM670/671NL + V717F) under the control of the hamster prion promoter (161), environmental enrichment likely counteracts the vascular dysfunction by increasing angiogenesis accompanied by upregulation of LRP1, apoE, and α2-macroglobulin, as well as downregulation of the receptor for advanced glycation end products, such that Aβ clearance is improved (162). Brain electroacupuncture also reduced hippocampal Aβ deposition and restored cognitive impairment in APP V717I transgenic mice, which was associated with an increase of hippocampal LRP1 (163). In addition, exercise ameliorated brain Aβ deposition and cognitive decline in APP transgenic mice concomitant with upregulations of LRP1 as well as neprilysin, insulin-degrading enzyme, matrix metallopeptidase 9, HSP70 (the 70 kDa heat shock proteins), or brain-derived neurotrophic factor (164, 165).
Several epidemiological studies indicate that HMG-CoA reductase inhibitors or statins, which are used to treat hypercholesterolemia, can reduce the risk of AD, in particular if they are given from middle age, although therapeutic effects of statins for AD patients appears to be moderate if any, which might be similar to anti-Aβ therapy (166). Interestingly, its oral administration has been demonstrated to promote Aβ clearance from the brain by increasing cerebrovascular LRP1 in wild-type mice and APP transgenic mice, which is likely mediated by the isoprenoid pathway (167). In wild-type mice or TgSwDI mice, which overexpress a triple mutant form of APP (KM670/671NL + E693Q + D694N) under the control of the mouse Thy1 promoter (168), oleocanthal, a phenolic secoiridoid component of extra virgin olive oil, upregulated p-glycoprotein and LRP1 at the BBB, resulting in enhanced Aβ clearance and reduction of neuroinflammation (169, 170). In vitro and in vivo experiments showed that cannabinoid treatment also enhanced Aβ transit at the BBB, associated with increased LRP1 levels in the brain and plasma (171). Oxidative and inflammatory stress might be involved in the pathogenesis of AD (172–175). Interestingly, antioxidant N-acetylcysteine protected against inflammation-induced dysfunction of Aβ clearance by LRP1 at the BBB (176). In addition, the administration of an α-secretase ADAM10 inhibitor, GI254023X, could enhance Aβ clearance through the BBB by reducing LRP1 shedding (177). Thus, pharmacological approaches to increase LRP1 in the cerebrovasculature may be promising strategies for AD therapy. However, increasing LRP1 alone may not be sufficient and cofactors are likely involved in the mechanisms (17). This might explain why mice deficient in vitamin E synthesis enzyme showed disturbed Aβ clearance from the brain despite increased LRP1 levels at brain vasculatures (98).
Interestingly, statin treatment also can upregulate LRP1 in the liver as well as brain (178). Oral administration of an Indian traditional drug, semi-purified extract of the root, Withania somnifera, increased liver LRP1 and ameliorated Aβ pathology in APP/PS1 mice likely by facilitating Aβ clearance across the BBB (99). Although further studies are needed, these results suggest that increasing liver LRP1 is potentially beneficial against brain Aβ accumulation, likely consistent with the peripheral sink hypothesis. Circulating sLRP1 may also be involved in the mechanism (32, 65). Of note, a therapeutic effect of modified sLRP1-like peptide, LRPIV-D3674G, which has a higher binding affinity to Aβ, but less binding affinity to other LRP1 ligands than wild-type sLRP1, was reported; subcutaneous administration of LRPIV-D3674G reduced Aβ40 and Aβ42 levels in the hippocampus, cortex, and CSF by 60–80%, and improved vascular and neuronal functions in Tg2576 mice (33). Thus, LRPIV-D3674G treatment can be a novel candidate for AD therapy directly targeting LRP1 function.
Although these treatments to increase LRP1 in brain, cerebrovasculature, liver, and plasma might be promising strategies for AD therapy, the effects should be carefully evaluated because LRP1 may exacerbate Aβ production/accumulation and enhance the cellular toxicity under some conditions, as described above. Further studies to address their impacts on more diverse endpoints through different intervention periods using multiple animal models would be desired to define potential LRP1-targeted therapy for AD. In addition, combination treatment with Aβ immunotherapy should also be explored as an alternative approach because intravenous injection of anti-Aβ antibody likely enhances Aβ clearance through LRP1 at the choroid plexus in APP transgenic mice (108).
SUMMARY AND PERSPECTIVE
Accumulating evidence through in vitro and in vivo studies has demonstrated that LRP1 critically regulates Aβ metabolism and brain homeostasis through multiple pathways in both apoE isoform-dependent and -independent manners. However, there are several discrepancies in those observations. It also remains to be clarified how much these pathways contribute to AD pathogenesis, because most of the findings were from cellular and animal models. Thus, further efforts should be devoted to comprehensively address: 1) the potential change of LRP1 levels/functions across specific stages of AD, especially at the preclinical stage, in human postmortem and antemortem cohorts; and 2) the potentially different roles of LRP1 depending on specific context, including cell types, ages, disease stages, and apoE isoforms. Clarifying these aspects should provide novel insights, enabling us to develop effective LRP1-targetted therapies for AD.
Acknowledgments
The authors thank Ms. Mary D. Davis for the careful reading of this manuscript.
Footnotes
Abbreviations:
- Aβ
- amyloid-β peptide
- AD
- Alzheimer’s disease
- APP
- amyloid precursor protein
- BBB
- blood-brain barrier
- CAA
- cerebral amyloid angiopathy
- CSF
- cerebrospinal fluid
- LDLR
- LDL receptor
- LRP
- LDL receptor-related protein
- MCI
- mild cognitive impairment
- NMDA
- N-methyl-D-aspartate
- sLRP1
- soluble form of LRP1
- PKC
- protein kinase C
- RAP
- receptor-associated protein
- VLDLR
- VLDL receptor
This work was supported by National Institutes of Health Grants P50AG016574, RF1AG051504, R01AG027924, R01AG035355, R01AG046205, and P01NS074969 (to G.B.), a grant from the Cure Alzheimer’s Fund (to G.B.), and fellowship supports from the Japan Heart Foundation, Naito Foundation, Mayo Clinic Alzheimer’s Disease Research Center, BrightFocus Foundation, and the National Alzheimer’s Coordinating Center (NACC) junior investigator award (to M.S.).
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