Ectodomain shedding of PLA2R1 is mediated by the metalloproteases ADAM10 and ADAM17.

Phospholipase A2 receptor 1 (PLA2R1) is a 180-kDa transmembrane protein that plays a role in inflammation and cancer and is the major autoantigen in membranous nephropathy, a rare but severe autoimmune kidney disease. A soluble form of PLA2R1 has been detected in mouse and human serum. It is likely produced by proteolytic shedding of membrane-bound PLA2R1 but the mechanism is unknown. Here, we show that human PLA2R1 is cleaved by A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 in HEK293 cells, mouse embryonic fibroblasts, and human podocytes. By combining site-directed mutagenesis and sequencing, we determined the exact cleavage site within the extracellular juxtamembrane stalk of human PLA2R1. Orthologs and paralogs of PLA2R1 are also shed. By using pharmacological inhibitors and genetic approaches with RNA interference and knock-out cellular models, we identified a major role of ADAM10 in the constitutive shedding of PLA2R1 and a dual role of ADAM10 and ADAM17 in the stimulated shedding. We did not observe evidence for cleavage by ß- or γ-secretase, suggesting that PLA2R1 may not be a substrate for regulated intramembrane proteolysis. PLA2R1 shedding occurs constitutively and can be triggered by the calcium ionophore ionomycin, the protein kinase C activator PMA, cytokines, and lipopolysaccharides, in vitro and in vivo. Altogether, our results show that PLA2R1 is a novel substrate for ADAM10 and ADAM17, producing a soluble form that is increased in inflammatory conditions and likely exerts various functions in physiological and pathophysiological conditions including inflammation, cancer, and membranous nephropathy.

The η-secretase-derived APP fragment ηCTF is localized in Golgi, endosomes and extracellular vesicles and contributes to Aß production.

The processing of the amyloid precursor protein (APP) is one of the key events contributing to Alzheimer's disease (AD) etiology. Canonical cleavages by ß- and γ-secretases lead to Aß production which accumulate in amyloid plaques. Recently, the matrix metalloprotease MT5-MMP, referred to as η-secretase, has been identified as a novel APP cleaving enzyme producing a transmembrane fragment, ηCTF that undergoes subsequent cleavages by α- and ß-secretases yielding the Aηα and AÎ·ß peptides, respectively. The functions and contributions of ηCTF and its related fragments to AD pathology are poorly understood. In this study, we designed a novel immunological probe referred to as ηCTF-NTer antibody that specifically interacts with the N-terminal part of ηCTF targeting ηCTF, Aηα, AÎ·ß but not C99, C83 and Aß. We examined the fate and localization of ηCTF fragment in various cell models and in mice. We found that overexpressed ηCTF undergoes degradation in the proteasomal and autophagic pathways and accumulates mainly in the Golgi and in endosomes. Moreover, we observed the presence of ηCTF in small extracellular vesicles purified from neuroblastoma cells or from mouse brains expressing ηCTF. Importantly, the expression of ηCTF in fibroblasts devoid on APP leads to Aß production demonstrating its contribution to the amyloidogenic pathway. Finally, we observed an ηCTF-like immunoreactivity around amyloid plaques and an age-dependent accumulation of ηCTF in the triple-transgenic mouse AD model. Thus, our study suggests that the ηCTF fragment likely contributes to AD pathology by its exosomal spreading and involvement in Aß production.

Therapeutic potential of parkin as a tumor suppressor via transcriptional control of cyclins in glioblastoma cell and animal models.

Parkin (PK) is an E3-ligase harboring tumor suppressor properties that has been associated to various cancer types including glioblastoma (GBM). However, PK is also a transcription factor (TF), the contribution of which to GBM etiology remains to be established. Methods: The impact of PK on GBM cells proliferation was analyzed by real-time impedance measurement and flow cytometry. Cyclins A and B proteins, promoter activities and mRNA levels were measured by western blot, luciferase assay and quantitative real-time PCR. Protein-protein and protein-promoter interactions were performed by co-immunoprecipitation and by ChIP approaches. The contribution of endogenous PK to tumor progression in vivo was performed by allografts of GL261 GBM cells in wild-type and PK knockout mice. Results: We show that overexpressed and endogenous PK control GBM cells proliferation by modulating the S and G2/M phases of the cell cycle via the trans-repression of cyclin A and cyclin B genes. We establish that cyclin B is regulated by both E3-ligase and TF PK functions while cyclin A is exclusively regulated by PK TF function. PK invalidation leads to enhanced tumor progression in immunocompetent mice suggesting an impact of PK-dependent tumor environment to tumor development. We show that PK is secreted by neuronal cells and recaptured by tumor cells. Recaptured PK lowered cyclins levels and decreased GBM cells proliferation. Further, PK expression is decreased in human GBM biopsies and its expression is inversely correlated to both cyclins A and B expressions. Conclusion: Our work demonstrates that PK tumor suppressor function contributes to the control of tumor by its cellular environment. It also shows a key role of PK TF function in GBM development via the control of cyclins in vitro and in vivo. It suggests that therapeutic strategies aimed at controlling PK shuttling to the nucleus may prove useful to treat GBM.

Dipeptidyl peptidase 4 contributes to Alzheimer's disease-like defects in a mouse model and is increased in sporadic Alzheimer's disease brains.

The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid ß peptides in Alzheimer's disease, is currently being questioned. In addition to full-length amyloid ß peptide, several N-terminally truncated fragments of amyloid ß peptide could well contribute to Alzheimer's disease setting and/or progression. Among them, pyroGlu3-amyloid ß peptide appears to be one of the main components of early anatomical lesions in Alzheimer's disease-affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid ß, but they appear as the rate-limiting enzymes yielding the Glu3-amyloid ß peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3-amyloid ß. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3-amyloid ß peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3-amyloid ß peptide and amyloid ß 42-positive plaques and amyloid ß 42 load in the triple transgenic Alzheimer's disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer's disease-related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer's disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3-amyloid ß peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer's disease progression.

Alzheimer's genetic risk factor FERMT2 (Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner.

Although APP metabolism is being intensively investigated, a large fraction of its modulators is yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimer's disease (AD), as a potential key modulator of axon guidance, a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism, and that FERMT2 underexpression impacts axonal growth, synaptic connectivity, and long-term potentiation in an APP-dependent manner. Last, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3'UTR of FERMT2, induced a downregulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 underexpression in neurons and insight into how this may influence AD pathogenesis.

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains.

Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer's disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the ß-secretase-derived APP-CTF fragment (C99) combined with ß- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aß triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with γ-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of Aß to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD.

The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer's Disease Models.

: Brains that are affected by Alzheimer's disease (AD) are characterized by the overload of extracellular amyloid ß (Aß) peptides, but recent data from cellular and animal models propose that Aß deposition is preceded by intraneuronal accumulation of the direct precursor of Aß, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α.

Obesity has been associated with cognitive decline, atrophy of brain regions related to learning and memory, and higher risk of developing dementia. However, the molecular mechanisms underlying these neurological alterations are still largely unknown. Here, we investigate the effects of palmitate, a saturated fatty acid present at high amounts in fat-rich diets, in the brain. Palmitate is increased in the cerebrospinal fluid (CSF) of overweight and obese patients with amnestic mild cognitive impairment. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Palmitate induces astroglial and microglial activation in the mouse hippocampus, and its deleterious impact is mediated by microglia-derived tumor necrosis factor alpha (TNF-α) signaling. Our results establish that obesity is associated with increases in CSF palmitate. By defining a pro-inflammatory mechanism by which abnormal levels of palmitate in the brain impair memory, the results further suggest that anti-inflammatory strategies may attenuate memory impairment in obesity.

Upregulation of the Sarco-Endoplasmic Reticulum Calcium ATPase 1 Truncated Isoform Plays a Pathogenic Role in Alzheimer's Disease.

Dysregulation of the Endoplasmic Reticulum (ER) Ca2+ homeostasis and subsequent ER stress activation occur in Alzheimer Disease (AD). We studied the contribution of the human truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T) to AD. We examined S1T expression in human AD-affected brains and its functional consequences in cellular and transgenic mice AD models. S1T expression is increased in sporadic AD brains and correlates with amyloid ß (Aß) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated ß-amyloid precursor protein (ßAPP) or treated with Aß oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and Aß through specific increases of ß-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and ßAPP-derived fragments that could contribute to AD setting and/or progression.

The OncoAge Consortium: Linking Aging and Oncology from Bench to Bedside and Back Again.

It is generally accepted that carcinogenesis and aging are two biological processes, which are known to be associated. Notably, the frequency of certain cancers (including lung cancer), increases significantly with the age of patients and there is now a wealth of data showing that multiple mechanisms leading to malignant transformation and to aging are interconnected, defining the so-called common biology of aging and cancer. OncoAge, a consortium launched in 2015, brings together the multidisciplinary expertise of leading public hospital services and academic laboratories to foster the transfer of scientific knowledge rapidly acquired in the fields of cancer biology and aging into innovative medical practice and silver economy development. This is achieved through the development of shared technical platforms (for research on genome stability, (epi)genetics, biobanking, immunology, metabolism, and artificial intelligence), clinical research projects, clinical trials, and education. OncoAge focuses mainly on two pilot pathologies, which benefit from the expertise of several members, namely lung and head and neck cancers. This review outlines the broad strategic directions and key advances of OncoAge and summarizes some of the issues faced by this consortium, as well as the short- and long-term perspectives.

Chronic fornix deep brain stimulation in a transgenic Alzheimer's rat model reduces amyloid burden, inflammation, and neuronal loss.

Recent studies have suggested deep brain stimulation (DBS) as a promising therapy in patients with Alzheimer's disease (AD). Particularly, the stimulation of the forniceal area was found to slow down the cognitive decline of some AD patients, but the biochemical and anatomical modifications underlying these effects remain poorly understood. We evaluated the effects of chronic forniceal stimulation on amyloid burden, inflammation, and neuronal loss in a transgenic Alzheimer rat model TgF344-AD, as well as in age-matched control rats. 18-month-old rats were surgically implanted with electrodes in stereotactic conditions and connected to a portable microstimulator for chronic DBS in freely moving rats. The stimulation was continuous during 5 weeks and animals were immediately sacrificed for immunohistochemical analysis of pathological markers. Implanted, but non-stimulated rats were used as controls. We found that chronic forniceal DBS in the Tg-AD rat significantly reduces amyloid deposition in the hippocampus and cortex, decreases astrogliosis and microglial activation and lowers neuronal loss, as determined by NeuN staining. In control animals, the stimulation neither affects neuroinflammation nor neuronal count. In the Tg-F344-AD rat model, 5 weeks of forniceal DBS decreased amyloidosis, inflammatory responses, and neuronal loss in both cortex and hippocampus. These findings strongly suggest a neuroprotective effect of DBS and support the beneficial effects of targeting the fornix in Alzheimer's disease patients.

Nuclear TP53: An unraveled function as transcriptional repressor of PINK1.

The tumor suppressor TP53/p53 is a key protein in both neurodegenerative diseases and cancer. Thus, TP53-linked cell death appears exacerbated in several age-related neuropathologies, while TP53 mutation-associated phenotypes indicate a loss of function accounting for approximately half of cancers. Thus, TP53 plays a pivotal role in these phenotypically distinct pathologies, a hypothesis reinforced by recent epidemiological studies suggesting an opposite risk to develop one type of pathology relative to the other. Dysfunctions in mitophagic processes also occur in both types of pathologies and again, TP53 has been proposed as one of the regulators of this cellular process. The consensus view postulates that TP53 exerts both anti- and pro-autophagy functions that are directly driven by a specific subcellular localization. Thus, TP53 positively modulates autophagy via the transcriptional control of several genes while it is acknowledged that its anti-autophagy phenotype is exclusively linked to a transcription-independent cytosolic control of an AMPK-MTOR cascade. Our study indicates that TP53 can also downregulate the specialized autophagy-related mitophagy response via the transcriptional repression of PINK1. This is the first demonstration of an anti-mitophagic control by nuclear TP53.

Nuclear p53-mediated repression of autophagy involves PINK1 transcriptional down-regulation.

p53 is a transcription factor that is implicated in the control of both apoptotic and autophagic cell death. This tumor suppressor elicits both pro-autophagic and anti-autophagic phenotypes depending of its intracellular localization. The ability of p53 to repress autophagy has been exclusively associated to its cytoplasmic localization. Here, we show that transcriptional activity of p53 also contributes to autophagy down-regulation. Thus, nuclear p53 controls PINK1, a key protein involved in the control of mitophagy, by repressing its promoter activity, protein and mRNA levels, ex-vivo and in vivo. We establish that deletion of an identified p53 responsive element on PINK1 promoter impacts p53-mediated PINK1 transcriptional repression and we demonstrate a p53-PINK1 physical interaction by chromatin immunoprecipitation. Accordingly, we show that only nuclear p53 accounts for its ability to repress PINK1 gene transcription. Further, we demonstrate ex-vivo and in vivo that p53 invalidation in human cells increases LC3 maturation as well as optineurin and NDP52 autophagy receptors expression and down-regulates TIM23, TOM20 and HSP60 mitophagy markers. Importantly, this phenotype is mimicked by TP53 invalidation in mice brain. Finally, by combining pharmacological and genetic approaches, we show that the p53-mediated negative regulation of autophagy is PINK1-dependent. Thus pifithrin-α-mediated blockade of p53 transcriptional activity enhances LC3 maturation and reduces p62, TIM23, TOM20 and HSP60 protein levels. This pifithrin-α-associated pro-mitophagy phenotype is fully abolished by PINK1 depletion. This data unravels a novel pathway by which nuclear p53 can repress autophagy/mitophagy that could underlie important dysfunctions in both neurodegenerative and cancer diseases.

ß-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog-Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models.

BACKGROUND: Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease-affected brains by yet unexplained mechanisms. METHODS: We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which presenilins control phosphatase and tensin homolog-induced kinase 1 (Pink-1) expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in adeno-associated virus-infected mice. Functional readout and mitochondrial physiology (mitochondrial potential) were assessed by combined procedures including flow cytometry, live imaging analysis, and immunohistochemistry. RESULTS: We show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, messenger RNA, and protein expression of Pink-1. This control is linked to γ-secretase activity and ß-amyloid precursor protein but is independent of phosphatase and tensin homolog. We show that amyloid precursor protein intracellular domain (AICD) accounts for presenilin-dependent phenotype and upregulates Pink-1 transactivation in cells as well as in vivo in a Forkhead box O3a-dependent manner. Interestingly, the modulation of γ-secretase activity or AICD expression affects Pink-1-related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control Pink-1 promoter transactivation and protein expression. CONCLUSIONS: Overall, we delineate a molecular cascade presenilins-AICD-Forkhead box O3a linking parkin to Pink-1. Our study demonstrates AICD-mediated Pink-1-dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin-Pink-1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions.

The Transcription Factor Function of Parkin: Breaking the Dogma.

PRKN (PARK2) is a key gene involved in both familial and sporadic Parkinson's disease that encodes parkin (PK). Since its discovery by the end of the 90s, both functional and more recently, structural studies led to a consensual view of PK as an E3 ligase only. It is generally considered that this function conditions the cellular load of a subset of cytosolic proteins prone to proteasomal degradation and that a loss of E3 ligase function triggers an accumulation of potentially toxic substrates and, consequently, a neuronal loss. Furthermore, PK molecular interplay with PTEN-induced kinase 1 (PINK1), a serine threonine kinase also involved in recessive cases of Parkinson's disease, is considered to underlie the mitophagy process. Thus, since mitochondrial homeostasis significantly governs cell health, there is a huge interest of the scientific community centered on PK function. In 2009, we have demonstrated that PK could also act as a transcription factor (TF) and induces neuroprotection via the downregulation of the pro-apoptotic and tumor suppressor factor, p53. Importantly, the DNA-binding properties of PK and its nuclear localization suggested an important role in the control of several genes. The duality of PK subcellular localization and of its associated ubiquitin ligase and TF functions suggests that PK could behave as a key molecular modulator of various physiological cellular signaling pathways that could be disrupted in pathological contexts. Here, we update the current knowledge on PK direct and indirect TF-mediated control of gene expression.

Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer's disease-like pathologies and cognitive deficits.

The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP +/- /PS1 +/-). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aß load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

Amyloid ß production is regulated by ß2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor.

Alteration of ryanodine receptor (RyR)-mediated calcium (Ca2+) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca2+ release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the ß-amyloid precursor protein (ßAPP) harboring the familial double Swedish mutations (APPswe). RyR2 macromolecular complex remodeling, characterized by depletion of the regulatory protein calstabin2, resulted in increased cytosolic Ca2+ levels and mitochondrial oxidative stress. We also report a functional interplay between amyloid ß (Aß), ß-adrenergic signaling, and altered Ca2+ signaling via leaky RyR2 channels. Thus, post-translational modifications of RyR occur downstream of Aß through a ß2-adrenergic signaling cascade that activates PKA. RyR2 remodeling in turn enhances ßAPP processing. Importantly, pharmacological stabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca2+ leakage, or blocking the ß2-adrenergic signaling cascade reduced ßAPP processing and the production of Aß in APPswe-expressing SH-SY5Y cells. We conclude that targeting RyR-mediated Ca2+ leakage may be a therapeutic approach to treat AD.

The transcription factor XBP1 in memory and cognition: Implications in Alzheimer disease.

X-box binding protein 1 (XBP1) is a unique basic region leucine zipper transcription factor isolated two decades ago in a search for regulators of major histocompatibility complex class II gene expression. XBP1 is a very complex protein regulating many physiological functions, including immune system, inflammatory responses, and lipid metabolism. Evidence over the past few years suggests that XBP1 also plays important roles in pathological settings since its activity as transcription factor has profound effects on the prognosis and progression of diseases such as cancer, neurodegeneration, and diabetes. Here we provide an overview on recent advances in our understanding of this multifaceted molecule, particularly in regulating synaptic plasticity and memory function, and the implications in neurodegenerative diseases with emphasis on Alzheimer disease.

Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.

Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a ß3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aß peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aß peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aß peptide production.

Localization and Processing of the Amyloid-ß Protein Precursor in Mitochondria-Associated Membranes.

Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-ß protein precursor (AßPP) and its proteolytic products in MAMs. We reveal that AßPP and its catabolites are present in MAMs in cellular models overexpressing wild type AßPP or AßPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both ß- and γ-secretases are present and harbor AßPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aß production and reversed by inhibiting ß- or γ-secretases. Using a proteomic approach, we show that AßPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AßPP processing and proteomic interactome in MAMs deregulation taking place in AD.