Mechanisms of Aβ Clearance and Degradation by Glial Cells

“…160 ApoE mutations (Verghese et al., 2013) Metal ions affect expression of IDE, NEP and metalloproteases (Sastre et al., 2015) ApoJ mutations (Harold et al., 2009) Insulin/diabetes affects IDE levels (Steneberg et al., 2013) Presenilin mutations affect microglia function (Farfara et al.,…”

“IDE is unequally expressed in human brain, majorly found in hypothalamic neurons and in hippocampus, cerebellum, and brain stem (Bernstein et al., 2008), coinciding with the location of insulin receptors in the brain.”

“The ubiquitin proteasome system (UPS) is a mechanism of protein degradation which selectively targets individual proteins, including short-lived, damaged, or defectively folded proteins (Rock et al., 1994; Lilienbaum, 2013).”

“It has been described that after being phagocytosed by microglia, Aβ can be degraded by cathepsin B (CAT-B) (Nakanishi, 2003; Halle et al., 2008).”

“Glial cells represent around 50% of the cells in the human brain (Azevedo et al., 2009).”

“This function seems to be associated with a special and particular phenotype in microglia (formally known as M2 or alternatively activated) in contrast with the pro-inflammatory M1 state (Tang and Le, 2016).”

“The FcRs have been shown to mediate Aβ clearance in the presence of anti-Aβ antibodies (Bard et al., 2000; Wilcock et al., 2003), as observed in Aβ immunization therapies (Bacskai et al., 2002).”

“Experimental data have suggested that Aβ and solutes can normally also be cleared along the lymphatic drainage pathways within the basement membranes of capillaries and arteries (Carare et al., 2008; Tarasoff-Conway et al., 2015).”

“The relevance of NEP and IDE has been proven in knockout models, whereby mice lacking those enzymes crossed with APP transgenic models show increased Aβ deposition (Iwata et al., 2001; Farris et al., 2003) in the brain.”

“NEP is mainly expressed in pre-synaptic terminals of neurons (Fukami et al., 2002) but can also be found in activated astrocytes (Fisk et al., 2007; Yamamoto et al., 2014) and microglia (Hickman et al., 2008).”

“However, it is clear that ApoE has a role on Aβ clearance because bexarotene, which enhances ApoE expression, clears Aβ and improves cognition in mice (Cramer et al., 2012).”

“…al., 2009) Insulin/diabetes affects IDE levels (Steneberg et al., 2013) Presenilin mutations affect microglia function (Farfara et al., 2011) Oxidative stress regulates IDE (Stocker and Keaney, 2004) TREM-2 mutations (Kleinberger et al., 2014) FIGURE 1 | Mechanisms of Aβ clearance by glial cells.”

“It was hypothesized that a defective clearance of Aβ-generating autophagic vacuoles creates conditions favorable for Aβ accumulation in AD and this is supported by data indicating that increasing autophagy by rapamycin reduces amyloid burden in vivo (Nixon, 2007).”

“There is evidence of an increase in the expression of β-APP cleaving enzyme-1 (BACE1), the enzyme responsible for the cleavage of the amyloid precursor protein (APP) in the amyloidogenic pathway, in sporadic AD cases (Holsinger et al., 2002; Yang et al., 2003).”

“It is widely accepted that microglia phagocytose fibrillar Aβ, particularly more vigorously when bound by the C3b complement system (Lee and Landreth, 2010).”

“Experimental data have suggested that Aβ and solutes can normally also be cleared along the lymphatic drainage pathways within the basement membranes of capillaries and arteries (Carare et al., 2008; Tarasoff-Conway et al., 2015).”

“Scavenger receptor type-A (SR-A), type B1 (SR-B1), CD36 and CD40 are able to bind and mediate the endocytosis of oligomeric and fibrillar Aβ (Paresce et al., 1996; Coraci et al., 2002; Husemann et al., 2002; El Khoury et al., 2003; Yang et al., 2011).”

“Other proteins with a crucial role in Aβ clearance are apolipoprotein E (ApoE) and α2-macroglobulin (α2-M); they interact with transporters including low-density lipoprotein Frontiers in Aging Neuroscience | www.frontiersin.org 1 July 2016 | Volume 8 | Article 160 receptor-related protein 1 (LRP1) receptors, very low-…”

“Formyl peptide receptors are a group of seven-transmembrane G protein coupled receptors (Le et al., 2002) and are expressed in neurons, microglia and astrocytes (Panaro et al., 2007; Braun et al., 2011).”

“TREM2 can activate phagocytosis in microglia and reduce TLR-mediated signaling in macrophages (Klesney-Tait et al., 2006).”

“…been implicated in the Frontiers in Aging Neuroscience | www.frontiersin.org 3 July 2016 | Volume 8 | Article 160 degradation of Aβ in these cells (Koistinaho et al., 2004), although it can be produced by microglia and neurons in response to stimuli from glial cells (Saura et al., 2003; Harris…”

“…1 (LRP1) receptors, very low-density lipoprotein receptor (VLDLR), and P-glycoprotein, localized in astrocytes and on the abluminal side of the cerebral endothelium, where they facilitate the transport of Aβ across the blood brain barrier (BBB) into the blood circulation (Deane et al., 2009).”

“However, some recent controversial reports indicate that ApoE does not bind Aβ but competes with Aβ for binding to LRP-1 in astrocytes, and this could impact Aβ clearance by glia and across the blood–brain barrier (BBB) (Verghese et al., 2013).”

“Fibrillar Aβ also acts as a scaffold for the assembly of a receptor complex consisting of CD36, alpha6beta1-integrin, and CD47 (Bamberger et al., 2003).”

“Toll-like receptors are involved in the microglial clearance of monomeric, oligomeric, and fibrillar Aβ (Tahara et al., 2006; Reed-Geaghan et al., 2009).”

“Scavenger receptor type-A (SR-A), type B1 (SR-B1), CD36 and CD40 are able to bind and mediate the endocytosis of oligomeric and fibrillar Aβ (Paresce et al., 1996; Coraci et al., 2002; Husemann et al., 2002; El Khoury et al., 2003; Yang et al., 2011).”

“Besides microglia, some types of SRs are expressed by astrocytes, including SR-BI and SR-MARCO (macrophage receptor with collagenous structure; Alarcon et al., 2005).”

“In addition, there is evidence that astrocytes are able to phagocytose neurons containing Aβ (Nagele et al., 2003).”

“Soluble Aβ can be cleared by microglia through fluid phase pinocytosis (Mandrekar et al., 2009), with spontaneous formation and internalization of pinosomes from membrane ruffles.”

“Scavenger receptor type-A (SR-A), type B1 (SR-B1), CD36 and CD40 are able to bind and mediate the endocytosis of oligomeric and fibrillar Aβ (Paresce et al., 1996; Coraci et al., 2002; Husemann et al., 2002; El Khoury et al., 2003; Yang et al., 2011).”

“Cho and colleagues reported the importance of autophagy in the clearance of extracellular Aβ fibrils by microglia and in the regulation of the Aβ-induced NLRP3 (NLR Family, Pyrin Domain Containing 3) inflammasome using microglia from atg7 knockout mice and in vitro cultures (Cho et al., 2014).”

“This activity was attenuated with specific inhibitors of MMP-2 and -9, as well as in ACM derived from mmp-2 or -9 knockout (KO) mice (Yin et al., 2006).”

“Matrix metalloproteinases, known to be expressed and secreted by astrocytes, play a role in the extracellular degradation of both monomeric and fibrillar forms of Aβ (Yan et al., 2006).”

“Some TLRs are also expressed in astrocytes and respond to TLR activators by secreting pro-inflammatory molecules (Gorina et al., 2009; van Noort and Bsibsi, 2009; Trudler et al., 2010).”

“…also involved in Aβ degradation, but whose relevance depends on the degree of Aβ pathology, are plasminogen activators and angiotensin-converting enzyme (ACE) (Hu et al., 2001), which are more effective for aggregated Aβ rather than regulating steady-state Aβ levels (Saido and Leissring, 2012).”

“Although RAGE receptors have been mainly involved in mediating the inflammatory cascade in activated microglia (Solito and Sastre, 2012), their role in Aβ phagocytosis in astrocytes has been recently demonstrated when blocking these receptors with specific antibodies (Jones et al., 2013).”

“Scavenger receptor type-A (SR-A), type B1 (SR-B1), CD36 and CD40 are able to bind and mediate the endocytosis of oligomeric and fibrillar Aβ (Paresce et al., 1996; Coraci et al., 2002; Husemann et al., 2002; El Khoury et al., 2003; Yang et al., 2011).”

“The phagocytosis of fibrillar Aβ(1–42) by microglia can also be mediated through the LPS receptor CD14, a coreceptor of the functional TLR complex (Liu et al., 2005).”

“The degree of involvement of Fc receptors in the clearance of Aβ bound by endogenous antibodies such as IgGs is currently not well elucidated (Doens and Fernández, 2014).”

“Neprilysin (NEP), the insulin degrading enzyme (IDE) and endothelin-converting enzymes-1 and -2 (ECE1 and ECE2) (Eckman et al., 2001, 2003) are metalloendopeptidases particularly involved in the degradation of monomeric Aβ species (although neprilysin can also hydrolyse oligomeric forms).”

“…(AD) has been associated with the presence of extracellular amyloid-β peptide (Aβ) aggregates, forming neuritic plaques, as well as intra-neuronal Aβ (Gouras et al., 2005; Blair et al., 2014), probably due to alterations in the mechanisms of generation and/or clearance of amyloid in the brain…”

“The FcRs have been shown to mediate Aβ clearance in the presence of anti-Aβ antibodies (Bard et al., 2000; Wilcock et al., 2003), as observed in Aβ immunization therapies (Bacskai et al., 2002).”

“Neprilysin (NEP), the insulin degrading enzyme (IDE) and endothelin-converting enzymes-1 and -2 (ECE1 and ECE2) (Eckman et al., 2001, 2003) are metalloendopeptidases particularly involved in the degradation of monomeric Aβ species (although neprilysin can also hydrolyse oligomeric forms).”

“The ubiquitin proteasome system (UPS) is a mechanism of protein degradation which selectively targets individual proteins, including short-lived, damaged, or defectively folded proteins (Rock et al., 1994; Lilienbaum, 2013).”

“…performed in TLR2 and TLR4 knockout mice have confirmed the importance of these receptors in Aβ clearance, showing increased Aβ deposition (Tahara et al., 2006; Richard et al., 2008; Frontiers in Aging Neuroscience | www.frontiersin.org 4 July 2016 | Volume 8 | Article 160 Birch et al., 2014).”

“Interestingly, the induction of microglial phagocytosis by fibrillar Aβ is attenuated by oligomeric Aβ (Pan et al., 2011).”

“There is evidence that the FPRL1/FPR2 subtype binds to Aβ(1–42) and activates microglial internalization of the Aβ/FPRL1 complex in a PLD dependent-manner in microglia (Le et al., 2001; Brandenburg et al., 2008) and astrocytes (Brandenburg et al., 2008).”

“Neprilysin (NEP), the insulin degrading enzyme (IDE) and endothelin-converting enzymes-1 and -2 (ECE1 and ECE2) (Eckman et al., 2001, 2003) are metalloendopeptidases particularly involved in the degradation of monomeric Aβ species (although neprilysin can also hydrolyse oligomeric forms).”

“It has been shown that ApoE binds Aβ, and this association is more efficient with the ApoE2 and E3 isoforms than with ApoE4; these complexes are thought to influence both seeding of fibrillar Aβ and transport of soluble Aβ (Wildsmith et al., 2013).”

“A great number of reviews have examined the main mechanisms of Aβ clearance and degradation (Bates et al., 2009; Saido and Leissring, 2012; Yoon and Jo, 2012; Tarasoff-Conway et al., 2015).”

“The FcRs have been shown to mediate Aβ clearance in the presence of anti-Aβ antibodies (Bard et al., 2000; Wilcock et al., 2003), as observed in Aβ immunization therapies (Bacskai et al., 2002).”

“In the brain, IDE is synthesized and secreted by neurons, oligodendrocytes, and microglia (Bernstein et al., 2008), where it is released via exosomes (Tamboli et al., 2010) especially acting on extracellular Aβ deposits.”

“A great number of reviews have examined the main mechanisms of Aβ clearance and degradation (Bates et al., 2009; Saido and Leissring, 2012; Yoon and Jo, 2012; Tarasoff-Conway et al., 2015).”

“While ACE is mainly neuronal, tissue plasminogen activator (tPA) is synthesized by neurons and microglial cells (Melchor and Strickland, 2005).”

“SR-As can act in conjunction with other receptors, such as complement receptor 3 (also known as Mac-1/CD11b) to promote the uptake of fibrillar Aβ in microglia (Fu et al., 2012).”

“In vitro and in vivo studies have shown that IDE and ECE are up-regulated in response to increasing levels of brain Aβ (Zhao et al., 2007), while NEP has been found reduced in AD brains (Wang et al., 2010).”

“These proteases cleave at different sites within the Aβ sequence, resulting in different enzymatic products (Nalivaeva et al., 2012).”

“In addition, ECE2 can be found expressed in endosomes/lysosomes where it can mediate the degradation of Aβ (Pacheco-Quinto and Eckman, 2013).”

“Besides microglia, some types of SRs are expressed by astrocytes, including SR-BI and SR-MARCO (macrophage receptor with collagenous structure; Alarcon et al., 2005).”

“It has been described that after being phagocytosed by microglia, Aβ can be degraded by cathepsin B (CAT-B) (Nakanishi, 2003; Halle et al., 2008).”

“NEP is mainly expressed in pre-synaptic terminals of neurons (Fukami et al., 2002) but can also be found in activated astrocytes (Fisk et al., 2007; Yamamoto et al., 2014) and microglia (Hickman et al., 2008).”

“Although RAGE receptors have been mainly involved in mediating the inflammatory cascade in activated microglia (Solito and Sastre, 2012), their role in Aβ phagocytosis in astrocytes has been recently demonstrated when blocking these receptors with specific antibodies (Jones et al., 2013).”

“…in the Frontiers in Aging Neuroscience | www.frontiersin.org 3 July 2016 | Volume 8 | Article 160 degradation of Aβ in these cells (Koistinaho et al., 2004), although it can be produced by microglia and neurons in response to stimuli from glial cells (Saura et al., 2003; Harris et al., 2004).”

“In addition, ECE2 can be found expressed in endosomes/lysosomes where it can mediate the degradation of Aβ (Pacheco-Quinto and Eckman, 2013).”

“In vessels, astrocyte end feet appear to connect to the smooth muscle layer (Morris et al., 2014).”

“The therapeutic approaches targeting these clearance mechanisms have provided promising results, including the design of vectors carrying genes for NEP, for instance, or the discovery of drugs that enhance the synthesis of ApoE, showing reductions in Aβ deposition and improving cognitive impairments.”

“…performed in TLR2 and TLR4 knockout mice have confirmed the importance of these receptors in Aβ clearance, showing increased Aβ deposition (Tahara et al., 2006; Richard et al., 2008; Frontiers in Aging Neuroscience | www.frontiersin.org 4 July 2016 | Volume 8 | Article 160 Birch et al., 2014).”

“…also involved in Aβ degradation, but whose relevance depends on the degree of Aβ pathology, are plasminogen activators and angiotensin-converting enzyme (ACE) (Hu et al., 2001), which are more effective for aggregated Aβ rather than regulating steady-state Aβ levels (Saido and Leissring, 2012).”

“Oligomeric and fibrillar Aβ are primarily internalized though receptor-mediated endocytosis, via a number of receptors that are expressed on the surface of microglia and astrocytes:”

“…affect expression of IDE, NEP and metalloproteases (Sastre et al., 2015) ApoJ mutations (Harold et al., 2009) Insulin/diabetes affects IDE levels (Steneberg et al., 2013) Presenilin mutations affect microglia function (Farfara et al., 2011) Oxidative stress regulates IDE (Stocker and Keaney,…”

“NEP is mainly expressed in pre-synaptic terminals of neurons (Fukami et al., 2002) but can also be found in activated astrocytes (Fisk et al., 2007; Yamamoto et al., 2014) and microglia (Hickman et al., 2008).”

“In addition, ECE2 can be found expressed in endosomes/lysosomes where it can mediate the degradation of Aβ (Pacheco-Quinto and Eckman, 2013).”

“In addition, there is evidence that astrocytes are able to phagocytose neurons containing Aβ (Nagele et al., 2003).”

“In addition, there is evidence that astrocytes are able to phagocytose neurons containing Aβ (Nagele et al., 2003).”

“…ApoE, ApoJ, ACT and a combination of SAP and complement C1q, a clear reduction in astrocytic but not microglial oligomeric Aβ uptake was observed (Mulder et al., 2014). α1-Antichymotrypsin (ACT) α1-Antichymotrypsin is a serine protease inhibitor that has been reported to bind Aβ and is…”

“…C1q, a clear reduction in astrocytic but not microglial oligomeric Aβ uptake was observed (Mulder et al., 2014). α1-Antichymotrypsin (ACT) α1-Antichymotrypsin is a serine protease inhibitor that has been reported to bind Aβ and is overexpressed in the brain of AD patients (Abraham, 2001).”

“…in the Frontiers in Aging Neuroscience | www.frontiersin.org 3 July 2016 | Volume 8 | Article 160 degradation of Aβ in these cells (Koistinaho et al., 2004), although it can be produced by microglia and neurons in response to stimuli from glial cells (Saura et al., 2003; Harris et al., 2004).”

“The therapeutic approaches targeting these clearance mechanisms have provided promising results, including the design of vectors carrying genes for NEP, for instance, or the discovery of drugs that enhance the synthesis of ApoE, showing reductions in Aβ deposition and improving cognitive impairments.”

“ECEs are expressed in neurons, endothelial cells (Naidoo et al., 2004), and astrocytes (Nakagomi et al., 2000) and primarily degrade Aβ intracellularly (Eckman et al., 2003).”

“ACT has been shown to be produced in astrocytes (Abraham et al., 1989) and its expression is regulated by proinflammatory cytokines including interleukin (IL)-1, oncostatin M (OSM), and complexes of IL-6, soluble IL6 receptors and transcriptional regulators such as nuclear factor 1-”

“In addition, both RAGE and SRMARCO are known to form complexes with FPRL1/FPR2 in the presence of Aβ, initiating microglial signaling cascades in response to Aβ (Brandenburg et al., 2010; Slowik et al., 2012).”

“Upon exposure to Aβ combined with ApoE, ApoJ, ACT and a combination of SAP and complement C1q, a clear reduction in astrocytic but not microglial oligomeric Aβ uptake was observed (Mulder et al., 2014). α1-Antichymotrypsin (ACT) α1-Antichymotrypsin is a serine protease inhibitor that has been…”

“…of rat brains were found to prevent Aβ42-induced learning and memory impairments and reduce Aβ42-induced glial inflammation and neuronal degeneration (Cascella et al., 2013), suppressing oligomer cytotoxicity. α2-M can act as a ligand for LRP-1 (Kanekiyo et al., 2014), promoting increased neurite…”

“It has been shown that the proteasomal degradation machinery is capable of cleaving Aβ(1–42) peptides in a dose-dependent manner, without significantly affecting the overall catalytic function of the proteasome (Zhao and Yang, 2010).”

“Astrocytes can also endocytose monomeric and oligomeric Aβ through actin regulation (Lee et al., 2015).”

“ECEs are expressed in neurons, endothelial cells (Naidoo et al., 2004), and astrocytes (Nakagomi et al., 2000) and primarily degrade Aβ intracellularly (Eckman et al., 2003).”

“…mutations (Harold et al., 2009) Insulin/diabetes affects IDE levels (Steneberg et al., 2013) Presenilin mutations affect microglia function (Farfara et al., 2011) Oxidative stress regulates IDE (Stocker and Keaney, 2004) TREM-2 mutations (Kleinberger et al., 2014) FIGURE 1 | Mechanisms of…”

“There is evidence that the FPRL1/FPR2 subtype binds to Aβ(1–42) and activates microglial internalization of the Aβ/FPRL1 complex in a PLD dependent-manner in microglia (Le et al., 2001; Brandenburg et al., 2008) and astrocytes (Brandenburg et al., 2008).”

“The relevance of NEP and IDE has been proven in knockout models, whereby mice lacking those enzymes crossed with APP transgenic models show increased Aβ deposition (Iwata et al., 2001; Farris et al., 2003) in the brain.”

“X and activator protein 1 (AP-1; Gopalan et al., 2006a,b). α2-Macroglobulin (α2-M) α2-Macroglobulin is a matrix metalloproteinase inhibitor that is also released by glial cells, in particular perivascular astrocytes (Cucullo et al., 2003).”

“Formyl peptide receptors are a group of seven-transmembrane G protein coupled receptors (Le et al., 2002) and are expressed in neurons, microglia and astrocytes (Panaro et al., 2007; Braun et al., 2011).”

“High expression of the channel aquaporin 4 (AQP-4) at the astrocyte end feet is thought to help solute clearance due to its role in water transport (Igarashi et al., 2014).”

“Some TLRs are also expressed in astrocytes and respond to TLR activators by secreting pro-inflammatory molecules (Gorina et al., 2009; van Noort and Bsibsi, 2009; Trudler et al., 2010).”

“X and activator protein 1 (AP-1; Gopalan et al., 2006a,b). α2-Macroglobulin (α2-M) α2-Macroglobulin is a matrix metalloproteinase inhibitor that is also released by glial cells, in particular perivascular astrocytes (Cucullo et al., 2003).”

“, 2002) but can also be found in activated astrocytes (Fisk et al., 2007; Yamamoto et al., 2014) and microglia (Hickman et al.”

“The transmembrane protein leucine-rich glioma inactivated protein 3 co-localizes with Aβ at the astrocytic cell membrane (Kimura et al., 2007), and its downregulation reduces Aβ internalization by astrocytes (Okabayashi and Kimura, 2008).”

“In the brain, IDE is synthesized and secreted by neurons, oligodendrocytes, and microglia (Bernstein et al., 2008), where it is released via exosomes (Tamboli et al., 2010) especially acting on extracellular Aβ deposits.”

“…been associated with the presence of extracellular amyloid-β peptide (Aβ) aggregates, forming neuritic plaques, as well as intra-neuronal Aβ (Gouras et al., 2005; Blair et al., 2014), probably due to alterations in the mechanisms of generation and/or clearance of amyloid in the brain during aging.”

“, 2014), promoting increased neurite outgrowth in primary sensory neurons (Yamauchi et al., 2013).”

“LRP-1 can also mediate Aβ phagocytosis in microglia, confirmed in vitro using LRP1 deficient cells (N’Songo et al., 2013).”

“Formyl peptide receptors are a group of seven-transmembrane G protein coupled receptors (Le et al., 2002) and are expressed in neurons, microglia and astrocytes (Panaro et al., 2007; Braun et al., 2011).”

“In addition, soluble Aβ can be cleared by proteolytic enzymes, such as metalloendopeptidases, plasminogen activators, matrix metalloproteinases, and lysosomal peptidases [96].”

“Astrocytes also express and secrete several MMPs, including MMP-2 and MMP-9, which degrade both monomeric and fibrillar extracellular forms of A β (Ries and Sastre, 2016).”

“Furthermore, since TREM2 is the most well-characterized Aβ receptor that activates Aβ endocytosis (Doens and Fernandez, 2014; Ries and Sastre, 2016; Ulland et al., 2017; Wang et al., 2015b; Zhao et al., 2018), we evaluated TREM2 recycling in primary microglia cells isolated from Rubicon−/− mice.”

“Although the mechanisms by which astrocytes react with Aβ remain largely elusive, astrocytes express a wide array of receptors, including the receptor for advanced glycation endproducts (RAGE), lipoprotein receptor-related proteins (LRPs), membrane-associated proteoglycans and scavenger receptor-like receptors, which…”

“Conversely, activation of these cells is important for the clearance of Aβ plaques through induction of phagocytosis (Ries and Sastre, 2016), demonstrating a dual role for neuroinflammation on Aβ pathology.”