Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome

Abstract

The accumulation of amyloid-β-containing neuritic plaques and intracellular tau protein tangles are key histopathological hallmarks of Alzheimer's disease (AD). This type of pathology clearly indicates that the mechanisms of neuronal housekeeping and protein quality control are compromised in AD. There is mounting evidence that the autophagosome-lysosomal degradation is impaired, which could disturb the processing of APP and provoke AD pathology. Beclin 1 is a molecular platform assembling an interactome with stimulating and suppressive components which regulate the initiation of the autophagosome formation. Recent studies have indicated that the expression Beclin 1 is reduced in AD brain. Moreover, the deficiency of Beclin 1 in cultured neurons and transgenic mice provokes the deposition of amyloid-β peptides whereas its overexpression reduces the accumulation of amyloid-β. There are several potential mechanisms, which could inhibit the function of Beclin 1 interactome and thus impair autophagy and promote AD pathology. The mechanisms include (i) reduction of Beclin 1 expression or its increased proteolytic cleavage by caspases, (ii) sequestration of Beclin 1 to non-functional locations, such as tau tangles, (iii) formation of inhibitory complexes between Beclin 1 and antiapoptotic Bcl-2 proteins or inflammasomes, (iv) interaction of Beclin 1 with inhibitory neurovirulent proteins, e.g. herpex simplex ICP34.5, or (v) inhibition of the Beclin 1/Vps34 complex through the activation of CDK1 and CDK5. We will shortly introduce the function of Beclin 1 interactome in autophagy and phagocytosis, review the recent evidence indicating that Beclin 1 regulates autophagy and APP processing in AD, and finally examine the potential mechanisms through which Beclin 1 dysfunction could be involved in the pathogenesis of AD.

Keywords: AD; ADAM10; ALS; AP1; APOE; APP; ASC; ATG; Ageing; Alzheimer's disease; Ambra1; AuTophaGy-related; Autophagy; B-cell lymphoma 2; B-cell lymphoma-extra large; BACE1; BAD; BAK; BAR; BAX; BCL2/adenovirus E1B 19kDa protein-interacting protein 3; BECN; BH3; BH3-only protein; BNIP3; BNIP3-like; Bax-interacting factor-1; Bcl-2; Bcl-2 antagonist killer; Bcl-2 interacting protein 1; Bcl-2-associated X protein; Bcl-2-associated death promoter; Bcl-2-homology-3 domain; Bcl-2-interacting protein; Bcl-xL; Beclin 1; Beclin 1 gene; Bif-1; Bim; Bin-Amphiphysin-Rvs domain; CARD9, BCL10, and MALT1 complex; CBM; CCD; CD46; CD46 antigen; CDK; CLU; Casp1; DAPK; DR; Drp1; ECD; EGF; ER; FK506 binding protein 38; FKBP38; FYVE finger-containing phosphoinositide kinase; Fis1; Forkhead box O; FoxO; GGA; GOPC; GSK3β; Golgi-associated PD2 and coiled-coil domains-containing protein; Golgi-associated PDZ and coiled-coil domains-containing protein; Golgi-associated, γ-adaptin ear-containing, ARF-binding protein; HIV; HMGB1; HSV; Hsp; ICP34.5; IFN; IL; IP3; JNK; LAMP2a; LC3; MCI; MIG-14; Mfn; Mitophagy; Myd88; N-methyl-D-aspartate; NACHT; NADPH oxidase 2; NF-κB; NIX; NLRP; NMDA; NO; NOD-like receptor family, pyrin domain containing; NOX2; Nef; Noxa; Nrf2; Opa1; PD; PERK; PI(3)P; PIKfyve; PINK1; PKD; PS; PSEN; PTEN-induced putative kinase 1; Parkin; Parkinson's disease; Phox; Pik3C3; Puma; RAS-related GTP-binding protein 7; RING-domain-containing E3 ubiquitin ligase; RIP1; ROS; RTN3; Rab7; SNARE; SNX; Slam family member 1; Slamf1; SorLA; Sortilin-related receptor; TAB; TAK1; TAK1 binding protein; TG2; TGFβ; TGFβ-activated kinase 1; TGN; TIR domain-containing adaptor inducing IFNβ; TLR; TNF receptor associated factor 6; TNF-related apoptosis-inducing ligand; TNF-α; TPC; TRAF6; TRAIL; TRIF; TRS1; Toll-like receptor; Tomm40; UBA; ULK1; UVRAG; Vps; Vps34; WD repeat domain phosphoinositide-interacting protein 1; WIPI-1; a disintegrin and metalloproteinase domain 10; activating molecule in Beclin 1-regulated autophagy; amyloid-β precursor protein; amyotrophic lateral sclerosis; apolipoprotein E gene; apoptosis-associated speck-like protein; c-Jun N-terminal kinase; caspase-1; clathrin adaptor-related protein; clusterin gene; coiled-coil domain; cyclin-dependent kinase; cytomegalovirus protein; death receptor; death-associated protein kinase; dynamin-related protein 1; endoplasmic reticulum; epidermal growth factor; eukaryotic translation initiation factor 2α kinase 3; evolutionarily conserved domain; glycogen synthase kinase 3β; heat shock protein; herpex simplex virus; high-mobility group protein B1; human immunodeficiency virus; infected cell protein 34.5; inositol 1,4,5-trisphosphate; interferon; interleukin; lysosome-associated membrane protein 2a; miR; microRNAs; microtubule-associated protein 1 light chain 3; mild cognitive impairment; mitochondrial fission 1 protein; mitofusin; myeloid differentiation primary response gene 88; nPIST; negative regulatory factor; neuronal isoform of protein-interacting specifically with TC10; nitric oxide; nuclear factor erythroid 2-like 2; nuclear factor-κB; nucleotide-binding and oligomerization domain; optic atrophy 1; phosphatidylinositol 3-kinase; phosphatidylinositol 3-phosphate; phosphoinositide-binding domain; presenilin; presenilin gene; protein kinase D; reactive oxygen species; receptor-interacting protein 1; reticulon 3; retromer cargo protein in C. elegans; soluble NSF attachment protein receptor; sorting nexin; trans-Golgi network; transforming growth factor β; transglutaminase 2; translocase of outer mitochondrial membrane 40 homolog; tumor necrosis factor-α; two pore segment channel 1; ubiquitin-associated domain; ultraviolet irradiation resistance-associated gene; unc-51-like kinase 1; vesicular protein-sorting protein; β-site amyloid-β A4 precursor protein-cleaving enzyme 1.