Kegg Pathway: Regulation of autophagy

Pharmacology. 2009 Nov 18; 85(1): 1-17
Tillement JP, Lecanu L, Papadopoulos V

Most neurodegenerative diseases share several clinical, genetic and pathophysiological features, and an irreversible evolution as well. They are characterized by an endogenous production of abnormal proteins called amyloid proteins (AP), which are not hydrosoluble, form depots, and are only partly cleared by autophagy and the ubiquitin-protease system. Despite their different structures, they are probably generated by a common pathological pathway, a misfolding process. This hypothesis suggests a common pharmacological approach, which can consist of either the blockade of the misfolding process, the elimination of AP or both. The currently validated treatments are mostly palliative ones, trying to supplant the function of destroyed neurons. New trends involve the Regulation of the cerebral cholesterol metabolism and the preservation of neuron mitochondrial functions. Special attention is given to already marketed drugs used for other indications, which are also able to act on neurodegeneration.

Cancer Res. 2009 Nov 17;
Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S, Khuri FR, Sun SY

Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in both preclinical studies and clinical trials. This activity is partly associated with its ability to inhibit Akt activity. It has been shown that the mammalian target of rapamycin (mTOR) axis plays a critical role in Regulation of cell proliferation and survival primarily through functioning both downstream and upstream of Akt. The current study reveals a novel mechanism by which perifosine inhibits Akt and the mTOR axis. In addition to inhibition of Akt, perifosine inhibited the assembly of both mTOR/raptor and mTOR/rictor complexes. Strikingly, perifosine reduced the levels of Akt and other major components including mTOR, raptor, rictor, 70-kDa ribosomal S6 kinase, and 4E-binding protein 1 in the mTOR axis by promoting their degradation through a GSK3/FBW7-dependent mechanism. These results thus suggest that perifosine inhibits the mTOR axis through a different mechanism from inhibition of mTOR signaling by classic mTOR inhibitors such as rapamycin. Moreover, perifosine substantially increased the levels of type II light chain 3, a hallmark of autophagy, in addition to increasing poly(ADP-ribose) polymerase cleavage, suggesting that perifosine induces both apoptosis and autophagy. The combination of perifosine with a lysosomal inhibitor enhanced apoptosis and inhibited the growth of xenografts in nude mice, suggesting that perifosine-induced autophagy protects cells from undergoing apoptosis. Collectively, we conclude that perifosine inhibits mTOR signaling and induces autophagy, highlighting a novel mechanism accounting for the anticancer activity of perifosine and a potential strategy to enhance the anticancer efficacy of perifosine by preventing autophagy. [Cancer Res 2009;69(23):8967-76].

Mol Cancer. 2009 Nov 12; 8(1): 100
Nakamura Y, Yogosawa S, Izutani Y, Watanabe H, Otsuji E, Sakai T

ABSTRACT: BACKGROUND: The chemopreventive effects of dietary phytochemicals on malignant tumors have been studied extensively because of a relative lack of toxicity. To achieve desirable effects, however, treatment with a single agent mostly requires high doses. Therefore, studies on effective combinations of phytochemicals at relatively low concentrations might contribute to chemopreventive strategies. RESULTS: Here we found for the first time that co-treatment with I3C and genistein, derived from cruciferous vegetables and soy, respectively, synergistically suppressed the viability of human colon cancer HT-29 cells at concentrations at which each agent alone was ineffective. The suppression of cell viability was due to the induction of a caspase-dependent apoptosis. Moreover, the combination effectively inhibited phosphorylation of Akt followed by dephosphorylation of caspase-9 or down-Regulation of XIAP and survivin, which contribute to the induction of apoptosis. In addition, the co-treatment also enhanced the induction of autophagy mediated by the dephosphorylation of mTOR, one of the downstream targets of Akt, whereas the maturation of autophagosomes was inhibited. These results give rise to the possibility that co-treatment with I3C and genistein induces apoptosis through the simultaneous inhibition of Akt activity and progression of the autophagic process. This possibility was examined using inhibitors of Akt combined with inhibitors of autophagy. The combination effectively induced apoptosis, whereas the Akt inhibitor alone did not. CONCLUSIONS: Although in vivo study is further required to evaluate physiological efficacies and toxicity of the combination treatment, our findings might provide a new insight into the development of novel combination therapies/chemoprevention against malignant tumors using dietary phytochemicals.

J Biol Chem. 2009 Nov 10;
Nakamura K, Kimple AJ, Siderovski DP, Johnson GL

p62/Sequestosome 1 is a scaffold protein involved in the Regulation of autophagy, trafficking of proteins to the proteasome, and activation of nuclear factor (NF)-kappaB. p62 encodes an N-terminal PB1 domain in addition to a ZZ, TBS, LIR and UBA domains, each critical for the physiological function of p62. PB1 domains have a beta-grasp topology where the front-end of one PB1 domain binds the back-end of a second PB1 domain. The p62 PB1 domain homodimerizes as well as heterodimerizes with other PB1 domains. The front-end of the PB1 domain in p62 binds the PB1 domain of atypical PKCs, the MAPK kinase, MEK5 and the NBR1 protein. Other than its role in homodimerization, the rear end acidic cluster region of the p62 PB1 domain had no previous defined binding partners. Herein, we demonstrate that the rear end acidic cluster region of the p62 PB1 domain binds the front end basic region of the MAPK kinase kinase, MEKK3. p62 and MEKK3 co-localize in speckles or aggregates that are centers for organizing TRAF6-regulated NF-kappaB signaling and the assembly of polyubiquinated proteins sorting to sequestosomes and proteasomes. The p62-MEKK3 complex binds TRAF6, which regulates the ubiquitination of the IKK complex and NF-kappaB activation. p62 is required for the association of MEKK3 with TRAF6 and shRNA knockdown of p62 inhibits IL-1 and MEKK3 activation of NF-kappaB. The rear end acidic cluster of the p62 PB1 domain is used to organize a cytosolic aggregates or speckles associated TRAF6-p62-MEKK3 complex for control of NF-kappaB activation.

EMBO J. 2009 Nov 5;
Webber JL, Tooze SA

autophagy, a lysosomal degradation pathway, is essential for homeostasis, development, neurological diseases, and cancer. Regulation of autophagy in human disease is not well understood. Atg9 is a transmembrane protein required for autophagy, and it has been proposed that trafficking of Atg9 may regulate autophagy. Mammalian Atg9 traffics between the TGN and endosomes in basal conditions, and newly formed autophagosomes in response to signals inducing autophagy. We identified p38IP as a new mAtg9 interactor and showed that this interaction is regulated by p38alpha MAPK. p38IP is required for starvation-induced mAtg9 trafficking and autophagosome formation. Manipulation of p38IP and p38alpha alters mAtg9 localization, suggesting p38alpha regulates, through p38IP, the starvation-induced mAtg9 trafficking to forming autophagosomes. Furthermore, we show that p38alpha is a negative regulator of both basal autophagy and starvation-induced autophagy, and suggest that this Regulation may be through a direct competition with mAtg9 for binding to p38IP. Our results provide evidence for a link between the MAPK pathway and the control of autophagy through mAtg9 and p38IP.

Cell Cycle. 2009 Dec 15; 8(23):
Rzymski T, Milani M, Singleton DC, Harris AL

Tumor hypoxia confers resistance to many modalities of anticancer therapy. The endoplasmic reticulum (ER) is highly sensitive to severe hypoxic stress and results in the activation of the unfolded protein response. ATF4 is the main transcriptional regulator of the cellular hypoxic response to the Unfolded Protein Response (UPR) and activates genes that promote restoration of normal ER function and survival under hypoxia. Elevated expression of ATF4 is associated with resistance to current chemotherapeutic drugs including DNA-interactive and damaging agents, nonsteroidal anti-inflammatory drugs and proteasome inhibitors. ATF4 decreases the antitumor activity of chemotherapy by mechanisms involving expression of genes involved in oxidative stress resistance, redox homeostasis and inhibitors of apoptosis. ATF4 plays also a crucial role in resistance to proteasomal inhibitor bortezomib (PS-341) by the induction of prosurvival pathways, such as autophagy, that can relieve the protein overload in bortezomib treated cells. Inhibition of ATF4 represents an attractive stand-alone therapy as well as an opportunity to enhance the efficacy of current chemotherapeutic agents without causing high tissue toxicity to normal tissues.

Am J Physiol Endocrinol Metab. 2009 Nov 3;
Kovsan J, Bashan N, Greenberg A, Rudich A

autophagy is a major degradative pathway(s) by which intracellular components are delivered into the lysosomes. It is largely implicated in determining cell death and survival, because it eliminates un-necessary, damaged, and/or potentially harmful cellular products and organelles, and is an important source for nutrients and energy production under conditions of external nutrient deficiency. As such, autophagy has been suggested to contribute to the Regulation of carbohydrate and protein metabolism during fasting. Recently, three papers implicated a role for autophagy in cellular lipid metabolism as well. This perspective article presents these novel findings in the context of prior studies on the role of autophagy and lysosomes in metabolic and energy Regulation, discusses their points of agreement and opposing propositions, and outlines key outstanding questions.

J Agric Food Chem. 2009 Nov 25; 57(22): 10612-10618
Arlorio M, Bottini C, Travaglia F, Locatelli M, Bordiga M, Coïsson JD, Martelli A, Tessitore L

Theobroma cacao L. is known to have potential cardiovascular and cancer chemopreventive activities because of its high content of phenolic phytochemicals and their antioxidant capacities. In this work, we show for the first time that cocoa inhibits drug-triggered liver cytotoxicity by inducing autophagy. Phenolic-rich extracts of both unroasted and roasted cocoa prevented Celecoxib-induced cell viability inhibition in MLP29 liver cells because of the accumulation of G1 cells and cell death. Death prevented by cocoa had hallmarks of apoptosis such as the sub-G1 peak at flow cytometry and activation of Bax expression, together with down-Regulation of Bcl-2, released cytochrome c in the cytosol with activation of Caspase 3, indicating that components of the apoptotic pathway such as Bax or upstream are major targets of cocoa phytochemicals. The protective effect of cocoa against liver cytotoxicity by Celecoxib was probably accounted for by inducing the autophagic process, as shown by enhanced Beclin 1 expression and accumulation of monodansylcadaverine in autolysosomes. This fact suggests that apoptosis was prevented by inducing autophagy. Finally, considering all these findings, we suggest that cocoa can be added to the list of natural chemopreventive agents whose potential in hepatopathy prevention and therapy should be evaluated.

FEBS J. 2009 Oct 26;
Lin Y, Hupp TR, Stevens C

Death-associated protein kinase (DAPK) is a stress-regulated protein kinase that mediates a range of processes, including signal-induced cell death and autophagy. Although the kinase domain of DAPK has a range of substrates that mediate its signalling, the additional protein interaction domains of DAPK are relatively ill defined. This review will summarize our current knowledge of the DAPK interactome, the use of peptide aptamers to define novel protein-protein interaction motifs, and how these new protein-protein interactions give insight into DAPK functions in diverse cellular processes, including growth factor signalling, the Regulation of autophagy, and its emerging role in the Regulation of immune responses.

Wei Sheng Wu Xue Bao. 2009 Jul 4; 49(7): 848-52
Yu Y, Wu B, Fang W

Vibrio parahaemolyticus is a halophilic gram-negative bacterium that causes food borne acute gastroenteritis in human being or certain diseases in aquatic species. In addition to thermostable direct hemolysin (tdh) and tdh-related hemolysin (trh), two sets of type III secretion systems (T3SS) were recently found to be associated closely with virulence. T3SS1 located on chromosome 1 is involved in cytotoxicity to host cells and orchestrates a multifaceted host cell infection by induction of autophagy, cell rounding, and eventual cell lysis. T3SS2 in chromosome 2 is enterotoxic. In this we address the composition of the two T3SS, their functions and Regulation in Vibrio parahaemolyticus.

Pathogenetics. 2009 Oct 28; 2(1): 6
Boletta A

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by the formation of renal cysts. This disease can be caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC-1) and -2 (PC-2), respectively. PC-1 is a large plasma membrane receptor involved in the Regulation of several biological functions and signaling pathways, and PC-2 is a calcium channel of the TRP family. The two proteins associate in a complex to prevent cyst formation, but the precise mechanism(s) involved remain largely unknown. This review will focus on recent advances in our understanding of the functions of polycystins and their role in signal transduction. Increased activity of the mammalian target of rapamycin (mTOR) kinase has been observed in cysts found in ADPKD tissues. Rapamycin has been shown to have beneficial effects in rodent models of polycystic kidney disease, prompting the initiation of pilot clinical trials with human patients. Furthermore, a direct role for PC-1 in the Regulation of cell growth (size) via mTOR has recently been demonstrated. Major advancements in the study of mTOR biology have highlighted that this kinase exists in association with two different complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTORC1 complex regulates cell growth (size), proliferation, translation and autophagy, and mTORC2 regulates the actin cytoskeleton and apoptosis. Interestingly, mTORC2 has been shown to contain the kinase responsible for the phosphorylation of Akt at Serine 473. Previous studies have shown that PC-1 controls the PI 3-kinase/Akt cascade to regulate apoptosis and the actin cytoskeleton, suggesting that this receptor might regulate mTOR at several levels. This review aims to discuss three different, inter-related themes emerging from the literature: (i) studies performed in our and other laboratories collectively suggest that PC-1 might be able to differentially regulate the two mTOR complexes; (ii) several studies point to genetic and functional cross-talk between the PKD and TSC genes, although the molecular details remain obscure; and (iii) studies performed in mammals and in the unicellular algae Chlamidomonas Reinhardtii might highlight a link between cilia, Regulation of cell size and Regulation of the cell cycle.

Nippon Rinsho. 2009 Oct; 67(10): 1869-74
Yokoyama T, Ohyashiki K

Leukemogenesis is thought to be a multistep process involving changes in the expression or abnormalities in the function of proteins encorded by a number of genes within the same cell. Such abnormalities affect the balance among cell proliferation, differentiation, and programmed cell death (PCD), and this lead to an expansion of the malignant clone. Apoptosis (type I PCD) and autophagy (type II PCD) are any form of cell death, mediated by an intracellular program, and involved in cell homeostasis. However, the mechanism of apoptosis and autophagy is extremely complex in leukemia cells, and the molecular machinery is still obscure. Therefore, understanding the Regulation of apoptotic and autophagic signaling pathways could provide important information for the development of novel therapies in leukemia cells.

J Biol Chem. 2009 Oct 22;
Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y, Imai H, Takeuchi T

Reactive oxygen species (ROS) are involved in several cell death processes including cerebral ischemic injury. We found that glutamate-induced ROS accumulation and the associated cell death in mouse hippocampal cell lines were delayed by pharmacological inhibition of autophagy or lysosomal activity. Glutamate, however, did not stimulate autophagy, which was assessed by a protein marker LC3, and neither changes in organization of mitochondria nor lysosomal membrane permeabilization were observed. Fluorescent analyses by a redox probe PF-H2TMRos revealed that autophagosomes and/or lysosomes are the major sites for basal ROS generation in addition to mitochondria. Treatments with inhibitors for autophagy and lysosomes decreased their basal ROS production and caused a burst of mitochondrial ROS to be delayed. On the other hand, attenuation of mitochondrial activity by serum depletion or by high cell-density culture resulted in the loss of both constitutive ROS production and a ROS burst in mitochondria. Thus, constitutive ROS production within mitochondria and lysosomes enables cells to be susceptible to glutamate-induced oxidative cytotoxicity. Corroboratively, inhibitors for autophagy and lysosomes reduced neural cell death in an ischemia model in rats. We suggest that cell injury during periods of ischemia is regulated by ROS-generating activity in autophagosomes and/or lysosomes as well as in mitochondria.

Soc Reprod Fertil Suppl. 2009; 66: 165-76
Prather RS, Ross JW, Clay Isom S, Green JA

Embryogenesis is a complex process that is controlled at various levels. As new discoveries are made about molecular mechanisms that control development in other species, it is apparent that these same mechanisms regulate pig embryogenesis as well. Methylation of DNA and modification of histones regulate transcription, and mechanisms such as ubiquitinization, autophagy and microRNAs regulate development post-transcriptionally. Each of these systems of Regulation is highly dynamic in the early embryo. A better understanding of each of these levels of Regulation can provide tools to potentially improve the reproductive process in pigs, to improve methods of creating pig embryos and cloned embryos in vitro, and to provide markers for predicting developmental competence of the embryo.

Clin Sci (Lond). 2010 Feb; 118(3): 173-81
Germain M, Slack RS

BCL-2 homologues are major regulators of apoptosis and, as such, play an active role in the survival of adult neurons following injury. In recent years, these proteins have also been associated with the Regulation of autophagy, a catabolic process involved in the recycling of nutrients upon starvation. Basal levels of autophagy are also required to eliminate damaged proteins and organelles. This is illustrated by the accumulation of ubiquitin-positive aggregates in cells deficient in autophagy and, in the nervous system, this is associated with progressive cell loss and signs of neurodegeneration. Given the importance of both apoptosis and autophagy for neuronal survival in adult neurons, understanding how BCL-2 homologues co-ordinately regulate these processes will allow a better understanding of the cellular processes leading to neurodegeneration. In the present review, we will discuss the roles of BCL-2 homologues in the Regulation of apoptosis and autophagy, focussing on their impact on adult neurons.

autophagy. 2009 Nov 16; 5(8):
Williams T, Forsberg LJ, Viollet B, Brenman JE

When ATP levels in a cell decrease, various homeostatic intracellular mechanisms initiate attempts to restore ATP levels. As a prominent energy sensor, AMP-activated protein kinase (AMPK) represents one molecular gauge that links energy levels to Regulation of anabolic and catabolic processes to restore energy balance. Although pharmacological studies have suggested that an AMPK activator, AIC AR (5-aminoimidazole-4-carboxamide ribonucleoside) may link AMPK activation to autophagy, a process that can provide short-term energy within the cell, AIC AR can have AMPK-independent effects. Therefore, using a genetic-based approach we investigated the role of AMPK in cellular energy balance. We demonstrate that genetically altered cells, mouse embryonic fibroblasts (MEFs), lacking functional AMPK, display altered energy balance under basal conditions and die prematurely under low glucose-serum starvation challenge. These AMPK mutant cells appear to be abnormally reliant on autophagy under low glucose basal conditions, and therefore cannot rely further on autophagy like wild-type cells during further energetic stress and instead undergo apoptosis. This data suggests that AMPK helps regulate basal energy levels under low glucose. Further, AMPK mutant cells show increased basal phosphorylation of p53 at serine 15, a residue phosphorylated under glucose deprivation. We propose that cells lacking AMPK function have altered p53 activity that may help sensitize these cells to apoptosis under energetic stress.

Nat Cell Biol. 2009 Nov; 11(11): 1355-62
Lee JS, Li Q, Lee JY, Lee SH, Jeong JH, Lee HR, Chang H, Zhou FC, Gao SJ, Liang C, Jung JU

autophagy is an active homeostatic degradation process for the removal or turnover of cytoplasmic components wherein the LC3 ubiquitin-like protein undergoes an Atg7 E1-like enzyme/Atg3 E2-like enzyme-mediated conjugation process to induce autophagosome biogenesis. Besides its cytoprotective role, autophagy acts on cell death when it is abnormally upregulated. Thus, the autophagy pathway requires tight Regulation to ensure that this degradative process is well balanced. Two death effector domains (DED1/2) containing cellular FLICE-like inhibitor protein (cFLIP) and viral FLIP (vFLIP) of Kaposi's sarcoma-associated herpesvirus (KSHV), Herpesvirus saimiri (HVS), and Molluscum contagiosum virus (MCV) protect cells from apoptosis mediated by death receptors. Here, we report that cellular and viral FLIPs suppress autophagy by preventing Atg3 from binding and processing LC3. Consequently, FLIP expression effectively represses cell death with autophagy, as induced by rapamycin, an mTor inhibitor and an effective anti-tumour drug against KSHV-induced Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). Remarkably, either a DED1 alpha2-helix ten amino-acid (alpha2) peptide or a DED2 alpha4-helix twelve amino-acid (alpha4) peptide of FLIP is individually sufficient for binding FLIP itself and Atg3, with the peptide interactions effectively suppressing Atg3-FLIP interaction without affecting Atg3-LC3 interaction, resulting in robust cell death with autophagy. Our study thus identifies a checkpoint of the autophagy pathway where cellular and viral FLIPs limit the Atg3-mediated step of LC3 conjugation to regulate autophagosome biogenesis. Furthermore, the FLIP-derived short peptides induce growth suppression and cell death with autophagy, representing biologically active molecules for potential anti-cancer therapies.

J Biol Chem. 2009 Oct 15;
Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ

CCL2 and IL-6 are among the most prevalent cytokines in the tumor microenvironment, with expression generally correlating with tumor progression and metastasis. CCL2 and IL-6 induced expression of each other in CD11b(+) cells isolated from human peripheral blood. It was demonstrated that both cytokines induce up-Regulation of the antiapoptotic proteins cFLIP(L) (cellular caspase-8 (FLICE)-like inhibitory protein), Bcl-2 and Bcl-X(L) and inhibit the cleavage of caspase-8 and subsequent activation of the caspase-cascade, thus protecting cells from apoptosis under serum deprivation stress. Furthermore, both cytokines induced hyper-activation of autophagy in these cells. Upon CCL2 or IL-6 stimulation, CD11b(+) cells demonstrated a significant increase in the mannose receptor (CD206) and the CD14(+)/CD206(+) double-positive cells, suggesting a polarization of macrophages towards the CD206(+) M2-type phenotype. Caspase-8 inhibitors mimicked the cytokine-induced up-Regulation of autophagy and M2 polarization. Furthermore, E64D and Leupeptin, which are able to function as inhibitors of autophagic degradation, reversed the effect of caspase-8 inhibitors in the M2-macrophage polarization, indicating a role of autophagy in this mechanism. Additionally, in patients with advanced castrate-resistant prostate cancer, metastatic lesions exhibited an increased CD14(+)/CD206(+) double-positive cell population, compared to normal tissues. Altogether, these findings suggest a role of CCL2 and IL-6 in the survival of myeloid monocytes recruited to the tumor microenvironment and their differentiation towards tumor-promoting M2-type macrophages via inhibition of caspase-8 cleavage and enhanced autophagy.

Curr Opin Gastroenterol. 2009 Nov; 25(6): 512-20
Heath RJ, Xavier RJ

PURPOSE OF REVIEW: To give an overview of autophagy and its effects on innate and adaptive immunity and touch on some of the roles of autophagy in disease. RECENT FINDINGS: Precise Regulation of autophagy is necessary to maintain metabolic equilibrium, immune homeostasis, delineate cell fate and influence host cell responses to cytosolic pathogens. A growing number of studies have implicated that inactivation of autophagy-selective responses contributes to inflammatory disorders, neurodegeneration and cancer, but the precise steps at which disease-associated autophagy-related (ATG) genes affect autophagy pathways is unknown at present. SUMMARY: In eukaryotic cells autophagy is constitutively active at low levels, whereas significant up-Regulation occurs in response to a multitude of stresses. autophagy has achieved notoriety as a perturbed biological process in many disease states and an exponential increase of studies attribute roles for autophagy in innate and adaptive immunity. Understanding how individual disease-associated ATG genes function will lead to a better understanding of and potentially novel therapies for treating the diseases in which they are involved.

Arterioscler Thromb Vasc Biol. 2009 Nov; 29(11): 1909-15
Hayashi S, Sato N, Yamamoto A, Ikegame Y, Nakashima S, Ogihara T, Morishita R

OBJECTIVE: Although the majority of cases of Alzheimer disease (AD) are known to be attributable to the sporadic (nongenetic) form of the disease, the mechanism underlying its cause and progression still remains unclear. METHODS AND RESULTS: We found that vascular beta-amyloid (Abeta), Abeta40, inhibited the proliferative activity of human brain vascular endothelial cells (HBECs) without toxic effects on them. This peptide also inhibited tube formation and migration of HBECs. Moreover, Abeta40 inhibited ex vivo hippocampal revascularization, reendothelialization, and the differentiation of adult endothelial progenitor cells. Importantly, Abeta40 suppressed the proliferative activity of HBECs through the induction of "self-digesting" autophagy. This induction involved the intracellular Regulation of class 3 phosphatidylinositol 3-kinase (PI3K) as well as Akt signaling in HBECs. Furthermore, tissue culture of murine brain sections from GFP-LC3 transgenic mice revealed that Abeta40 not only reduced the vessel density in hippocampal lesions, but also induced autophagy in neurovascular ECs. CONCLUSIONS: Our present findings indicate that the initial progression of AD might be in part driven by Abeta40-induced endothelial autophagy and impairment of neurovascular regeneration, suggesting important implications for therapeutic approaches to AD.