Figure 1. Schematic representation of regulatory mechanisms of lncRNAs during APP processing and Aβ production. lncRNAs are first produced in the endoplasmic reticulum, modified by Golgi processing, and transported to the plasma membrane, where they primarily enter the nonamyloid processing pathway (green box). lncRNAs are internalized from the plasma membrane to form early endonucleosomes, from where they: (1) Can be transported again to the plasma membrane to enter the recycling pathway, (2) Can be returned to the TGN via the reverse-transcriptase-mediated pathway, (3) Can form late intranucleosomes that enter the amyloid processing pathway (green box) or fuse with lysosomes for degradation; the above pathways are indicated by pink arrows. Grey circles marked with numbers 1–4 represent APP processing and Aβ production with the involvement of SORL1. lncRNAs regulate APP processing and Aβ production by a variety of specific mechanisms, including mRNA transcription (NDM29 and BC200), mRNA splicing (51A and 17A), miRNA sponges (BACE-AS, NEAT1, XIST, BDNF-AS, and MAG22-AS), mRNA stability (BACE1-AS), and protein activity (NDM29).

Figure 1. Schematic representation of regulatory mechanisms of lncRNAs during APP processing and Aβ production. lncRNAs are first produced in the endoplasmic reticulum, modified by Golgi processing, and transported to the plasma membrane, where they primarily enter the nonamyloid processing pathway (green box). lncRNAs are internalized from the plasma membrane to form early endonucleosomes, from where they: (1) Can be transported again to the plasma membrane to enter the recycling pathway, (2) Can be returned to the TGN via the reverse-transcriptase-mediated pathway, (3) Can form late intranucleosomes that enter the amyloid processing pathway (green box) or fuse with lysosomes for degradation; the above pathways are indicated by pink arrows. Grey circles marked with numbers 1–4 represent APP processing and Aβ production with the involvement of SORL1. lncRNAs regulate APP processing and Aβ production by a variety of specific mechanisms, including mRNA transcription (NDM29 and BC200), mRNA splicing (51A and 17A), miRNA sponges (BACE-AS, NEAT1, XIST, BDNF-AS, and MAG22-AS), mRNA stability (BACE1-AS), and protein activity (NDM29).

Figure 2. Mechanisms of lncRNA in Aβ clearance pathway. (A) Overview of Aβ clearance pathway. (B) Schematic representation of LRP1-mediated endocytosis in microglia, astrocytes, and neurons. Schematic representation of LRP1/P-gp-mediated transmigration of brain microvascular endothelial cells in BBB. This process primarily involves Aβ being internalized by LRP1 on brain microvascular endothelial cells in BBB and delivered to P-gp, which then secretes Aβ on the luminal side of BMEC, while LRP1 is recycled to the cell surface. (C) Specific mechanisms in the regulation of Aβ clearance by lncRNAs. In early AD, downregulation of lncRNA NEAT1 reduces glial-cell-mediated Aβ clearance through epigenetic histone modifications that inhibit the expression of endocytosis-related genes (CAV2, TGFB2, and TGFBR1). In AD, lncRNA XIST expression is increased, leading to reduced NEP expression via increasing enrichment of EZH2 and H3K27me3 in the NEP promoter region, thereby inhibiting enzymatic clearance of Aβ in cells. lncRNA LRP1-AS expression is increased in AD, and it directly binds to Hmgb2 and inhibits the Hmgb2-enhanced Srebp1a transcriptional activity on LRP1, thereby inhibiting LRP1 expression and thereby reducing glial- and neuronal-mediated Aβ clearance.

Figure 2. Mechanisms of lncRNA in Aβ clearance pathway. (A) Overview of Aβ clearance pathway. (B) Schematic representation of LRP1-mediated endocytosis in microglia, astrocytes, and neurons. Schematic representation of LRP1/P-gp-mediated transmigration of brain microvascular endothelial cells in BBB. This process primarily involves Aβ being internalized by LRP1 on brain microvascular endothelial cells in BBB and delivered to P-gp, which then secretes Aβ on the luminal side of BMEC, while LRP1 is recycled to the cell surface. (C) Specific mechanisms in the regulation of Aβ clearance by lncRNAs. In early AD, downregulation of lncRNA NEAT1 reduces glial-cell-mediated Aβ clearance through epigenetic histone modifications that inhibit the expression of endocytosis-related genes (CAV2, TGFB2, and TGFBR1). In AD, lncRNA XIST expression is increased, leading to reduced NEP expression via increasing enrichment of EZH2 and H3K27me3 in the NEP promoter region, thereby inhibiting enzymatic clearance of Aβ in cells. lncRNA LRP1-AS expression is increased in AD, and it directly binds to Hmgb2 and inhibits the Hmgb2-enhanced Srebp1a transcriptional activity on LRP1, thereby inhibiting LRP1 expression and thereby reducing glial- and neuronal-mediated Aβ clearance.

Figure 3. Complexity and interactions of lncRNAs in Aβ cascade hypothesis. Gray lines represent the ceRNA axis of lncRNAs. Black lines represent other mechanisms of action of lncRNAs, including mRNA transcription (NDM29, BC200, and LRP-AS), mRNA splicing (51A and 17A), and histone modification (NEAT1, XIST, and BDNF-AS).

Figure 3. Complexity and interactions of lncRNAs in Aβ cascade hypothesis. Gray lines represent the ceRNA axis of lncRNAs. Black lines represent other mechanisms of action of lncRNAs, including mRNA transcription (NDM29, BC200, and LRP-AS), mRNA splicing (51A and 17A), and histone modification (NEAT1, XIST, and BDNF-AS).

Table 1. Aberrant expression patterns of various lncRNAs involved in Aβ cascade hypothesis.

Table 1. Aberrant expression patterns of various lncRNAs involved in Aβ cascade hypothesis.

LncRNALevelRegulatory ModeMechanismEffects on ADReferenceBACE1-ASupmodulate mRNA stabilitypairs with BACE1 mRNA to form RNA duplexes, leading to structural changes and enhanced stability of BACE1 mRNApromotes Aβ production[51] miRNA spongeincrease the level of BACE1 mRNA by binding to miR-485-5p as a ceRNA [52] acts as a ceRNA by sponging miR-214-3p and regulating ATG5 expression, promoting autophagy-mediated neuronal damagepromotes Aβ-induced neurotoxicity[56] targets miR-132-3p [57]MAGI2-AS3upmiRNA spongeincreases the level of BACE1 mRNA by binding to miR-374b-5p as a ceRNA promotes Aβ production[14]BC200upmodulate mRNA transcriptionincrease the level of BACE1 mRNA and proteinpromotes Aβ production[66]17Aupsplicing modulationinhibits the transcription of the canonical isoform of GABAB R2 by affecting GPR51 alternative splicing and impairs the GABAB signaling pathwaypromotes Aβ production[68]NDM29upmodulate mRNA transcriptionincreases the level of APP mRNA and proteinpromotes Aβ production[92] modulation protein activityincreases β- and γ-secretase activities [92]51Aupsplicing modulationbinds to the splice site of SORL1 pre-mRNA via base-pairing, resulting in a splice shift that reduces the expression of the canonical variant Apromotes Aβ production[85]BDNF-ASupmiRNA spongeincrease the level of BACE1 mRNA by binding to miR-9-5p as a ceRNApromotes Aβ production[121] histone modificationrecruits Ezh2 to the BDNF promoter region to catalyze the trimethylation of histone H3-lysine 27 (H3K27met3), repressing transcription of BDNF mRNApromotes Aβ-induced neurotoxicity[120]LRP1-ASupModulate mRNA transcriptionbinds directly to Hmgb2 and suppresses Hmgb2-enhanced Srebp1a transcriptional activity on LRP1inhibit Aβ clearance[132]NEAT1upmiRNA spongeincrease the level of BACE1 mRNA by binding to miR-124 as a ceRNA promote Aβ production[136] protects ROR1 by binding to 146a-5p and 34a-5p as a ceRNAinhibits Aβ-induced neurotoxicity[197]NEAT1downhistone modification inhibits acetyl-CoA generation and autoacetylation of P300, and then decreases H3K27Ac and increases H3K27Cro nearby the TSS of endocytosis-associated genes to inhibit endocytosis-associated genes expressioninhibit Aβ clearance[137]XISTupmiRNA spongeincrease the level of BACE1 mRNA by binding to miR-124 as a ceRNApromote Aβ production[145] targets miR-132promotes Aβ-induced neurotoxicity[198] histone modificationrecruits Ezh2 to the NEP promoter region to catalyzes the trimethylation of H3K27met3, repressing transcription of NEP mRNAinhibit Aβ clearance[144]ATBupmiRNA spongeacts as a ceRNA by sponging miR-200 and regulating ZNF217 expressionpromotes Aβ-induced neurotoxicity[147]RPPH1upmiRNA spongeacts as a ceRNA by sponging miR-326 and regulating PKM2 expressioninhibits Aβ-induced neurotoxicity[151] acts as a ceRNA by targeting miR-122 and activating downstream Wnt/β-catenin signalingpromotes Aβ-induced neurotoxicity[152]H19upmiRNA spongeActs as a ceRNA by sponging miR-124 and regulating HMGB1 expressionpromotes Aβ-induced neurotoxicity[158]SNHG1upmiRNA spongeActs as a ceRNA by sponging miR-361-3p and regulating ZNF217 expressionpromotes Aβ-induced neurotoxicity[160] Acts as a ceRNA by sponging miR-137and regulating KREMEN1 expression [161]WT1-ASdown-regulates the transcription factor WT1 to inhibit the miR-375/SIX4 axisinhibits Aβ-induced neurotoxicity[164]EBF3-ASup-negatively regulates EBF3promotes Aβ-induced neurotoxicity[166]SNHG19upmiRNA spongeActs as a ceRNA by sponging miR-137 and regulating TNFAIP1 expression promotes Aβ-induced neurotoxicity[170]SOX21-AS1upmiRNA spongeActs as a ceRNA by sponging the miR-132 axis to regulate PI3K/AKT pathwaypromotes Aβ-induced neurotoxicity[174] negatively regulate miR-107 [173] -upregulates the expression of FZD3/5 and activates the Wnt signaling pathway [172]SNHG7upmiRNA spongeacts as a ceRNA to regulate the miR-17-5p/NFATC3 signaling pathway and to inhibit TJ-related protein expression.promotes Aβ-induced neurotoxicity[180]ANRILupmiRNA spongetargets miR-125a [182]MALAT1downmiRNA spongeregulates the expression of receptor tyrosine kinase EPHA2 via sponging miR-200a/26a/26binhibits Aβ-induced neurotoxicity[192] Acts as a ceRNA by sponging miR-30b and regulated CNR1 expression [190]