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1. Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice

Author

Sasmita, Andrew Octavian, Depp, Constanze, Nazarenko, Taisiia, Sun, Ting, Siems, Sophie B., Ong, Erinne Cherisse, Nkeh, Yakum B., Böhler, Carolin, Yu, Xuan, Bues, Bastian, Evangelista, Lisa, Mao, Shuying, Morgado, Barbara, Wu, Zoe, Ruhwedel, Torben, Subramanian, Swati, Börensen, Friederike, Overhoff, Katharina, Spieth, Lena, Berghoff, Stefan A., Sadleir, Katherine Rose, Vassar, Robert, Eggert, Simone, Goebbels, Sandra, Saito, Takashi, Saido, Takaomi, Saher, Gesine, Möbius, Wiebke, Castelo-Branco, Gonçalo, Klafki, Hans-Wolfgang, Wirths, Oliver, Wiltfang, Jens, Jäkel, Sarah, Yan, Riqiang, and Nave, Klaus-Armin

Published
2024
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2. Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging

Author

Paudel, Bidur, Jeong, Si-Yeon, Martinez, Carolina Pena, Rickman, Alexis, Haluck-Kangas, Ashley, Bartom, Elizabeth T., Fredriksen, Kristina, Affaneh, Amira, Kessler, John A., Mazzulli, Joseph R., Murmann, Andrea E., Rogalski, Emily, Geula, Changiz, Ferreira, Adriana, Heckmann, Bradlee L., Green, Douglas R., Sadleir, Katherine R., Vassar, Robert, and Peter, Marcus E.

Published
2024
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3. LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Author

Katsumata, Yuriko, Fardo, David W, Shade, Lincoln MP, Bowen, James D, Crane, Paul K, Jarvik, Gail P, Keene, C Dirk, Larson, Eric B, McCormick, Wayne C, McCurry, Susan M, Mukherjee, Shubhabrata, Kowall, Neil W, McKee, Ann C, Honig, Robert A, Lawrence, S, Vonsattel, Jean Paul, Williamson, Jennifer, Small, Scott, Burke, James R, Hulette, Christine M, Welsh-Bohmer, Kathleen A, Gearing, Marla, Lah, James J, Levey, Allan I, Wingo, Thomas S, Apostolova, Liana G, Farlow, Martin R, Ghetti, Bernardino, Saykin, Andrew J, Spina, Salvatore, Albert, Marilyn S, Lyketsos, Constantine G, Troncoso, Juan C, Frosch, Matthew P, Green, Robert C, Growdon, John H, Hyman, Bradley T, Tanzi, Rudolph E, Potter, Huntington, Dickson, Dennis W, Ertekin-Taner, Nilufer, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Duara, Ranjan, Buxbaum, Joseph D, Goate, Alison M, Sano, Mary, Masurkar, Arjun V, Wisniewski, Thomas, Bigio, Eileen H, Mesulam, Marsel, Weintraub, Sandra, Vassar, Robert, Kaye, Jeffrey A, Quinn, Joseph F, Woltjer, Randall L, Barnes, Lisa L, Bennett, David A, Schneider, Julie A, Yu, Lei, Henderson, Victor, Fallon, Kenneth B, Harrell, Lindy E, Marson, Daniel C, Roberson, Erik D, DeCarli, Charles, Jin, Lee-Way, Olichney, John M, Kim, Ronald, LaFerla, Frank M, Monuki, Edwin, Head, Elizabeth, Sultzer, David, Geschwind, Daniel H, Vinters, Harry V, Chesselet, Marie-Francoise, Galasko, Douglas R, Brewer, James B, Boxer, Adam, Karydas, Anna, Kramer, Joel H, Miller, Bruce L, Rosen, Howard J, Seeley, William W, Burns, Jeffrey M, Swerdlow, Russell H, Abner, Erin, Van Eldik, Linda J, Albin, Roger L, Lieberman, Andrew P, Paulson, Henry L, Arnold, Steven E, Trojanowski, John Q, Van Deerlin, Vivianna M, Hamilton, Ronald L, Kamboh, M Ilyas, Lopez, Oscar L, and Becker, James T

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Acquired Cognitive Impairment, Prevention, Aging, Minority Health, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Health Disparities, Genetics, 2.1 Biological and endogenous factors, Aetiology, Humans, Alleles, Polymorphism, Single Nucleotide, Alzheimer Disease, TDP-43 Proteinopathies, Progranulins, Membrane Proteins, Nerve Tissue Proteins, Sulfonylurea Receptors, Alzheimer’s Disease Genetics Consortium, KCNMB2, Diversity, Epidemiology, FTLD, Genome-Wide Association Studies, KATP, Neurology & Neurosurgery, Clinical sciences
Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Published
2023

4. AD-BERT: Using Pre-trained contextualized embeddings to Predict the Progression from Mild Cognitive Impairment to Alzheimer's Disease

Author

Mao, Chengsheng, Xu, Jie, Rasmussen, Luke, Li, Yikuan, Adekkanattu, Prakash, Pacheco, Jennifer, Bonakdarpour, Borna, Vassar, Robert, Jiang, Guoqian, Wang, Fei, Pathak, Jyotishman, and Luo, Yuan

Subjects
Computer Science - Computation and Language, Computer Science - Machine Learning
Abstract

Objective: We develop a deep learning framework based on the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model using unstructured clinical notes from electronic health records (EHRs) to predict the risk of disease progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Materials and Methods: We identified 3657 patients diagnosed with MCI together with their progress notes from Northwestern Medicine Enterprise Data Warehouse (NMEDW) between 2000-2020. The progress notes no later than the first MCI diagnosis were used for the prediction. We first preprocessed the notes by deidentification, cleaning and splitting, and then pretrained a BERT model for AD (AD-BERT) based on the publicly available Bio+Clinical BERT on the preprocessed notes. The embeddings of all the sections of a patient's notes processed by AD-BERT were combined by MaxPooling to compute the probability of MCI-to-AD progression. For replication, we conducted a similar set of experiments on 2563 MCI patients identified at Weill Cornell Medicine (WCM) during the same timeframe. Results: Compared with the 7 baseline models, the AD-BERT model achieved the best performance on both datasets, with Area Under receiver operating characteristic Curve (AUC) of 0.8170 and F1 score of 0.4178 on NMEDW dataset and AUC of 0.8830 and F1 score of 0.6836 on WCM dataset. Conclusion: We developed a deep learning framework using BERT models which provide an effective solution for prediction of MCI-to-AD progression using clinical note analysis.

Published
2022

9. The β-Secretase BACE1 in Alzheimer’s Disease

Author

Hampel, Harald, Vassar, Robert, De Strooper, Bart, Hardy, John, Willem, Michael, Singh, Neeraj, Zhou, John, Yan, Riqiang, Vanmechelen, Eugeen, De Vos, Ann, Nisticò, Robert, Corbo, Massimo, Imbimbo, Bruno Pietro, Streffer, Johannes, Voytyuk, Iryna, Timmers, Maarten, Tahami Monfared, Amir Abbas, Irizarry, Michael, Albala, Bruce, Koyama, Akihiko, Watanabe, Naoto, Kimura, Teiji, Yarenis, Lisa, Lista, Simone, Kramer, Lynn, and Vergallo, Andrea

Subjects
Biochemistry and Cell Biology, Biological Sciences, Neurosciences, Acquired Cognitive Impairment, Aging, Alzheimer's Disease, Brain Disorders, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Neurodegenerative, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Aspartic Acid Endopeptidases, Humans, Mice, Mice, Knockout, Alzheimer’s disease, BACE1 inhibitors, Biomarkers, Clinical trials, Soluble amyloid, Synaptic, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-β (Aβ), including Aβ42, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aβ and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aβ in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.

Published
2021

14. BACE Inhibitor Clinical Trials for Alzheimer's Disease.

Author

Watkins, Elyse A. and Vassar, Robert

Subjects
*PROTEIN precursors, *ALZHEIMER'S disease, *PEPTIDES, *SMALL molecules, *CLINICAL trials
Abstract

The amyloid hypothesis posits that the amyloid-β aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer's disease. Recent clinical trials of passive immunotherapy with anti-amyloid-β antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-β protein precursor (AβPP) into amyloid-β peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although effective in preventing amyloid-β production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer's disease. Aside from AβPP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Gut microbiome‐derived metabolites in Alzheimer's disease: Regulation of immunity and potential for therapeutics.

Author

Chandra, Sidhanth and Vassar, Robert J.

Subjects
*ALZHEIMER'S disease, *MICROBIAL metabolites, *IMMUNOREGULATION, *GUT microbiome, *NEURODEGENERATION
Abstract

Summary Alzheimer's disease (AD) is the most common neurodegenerative disorder and cause of dementia. Despite the prevalence of AD, there is a lack of effective disease modifying therapies. Recent evidence indicates that the gut microbiome (GMB) may play a role in AD through its regulation of innate and adaptive immunity. Gut microbes regulate physiology through their production of metabolites and byproducts. Microbial metabolites may be beneficial or detrimental to the pathogenesis and progression of inflammatory diseases. A better understanding of the role GMB‐derived metabolites play in AD may lead to the development of therapeutic strategies for AD. In this review, we summarize the function of bioactive GMB‐derived metabolites and byproducts and their roles in AD models. We also call for more focus on this area in the gut–brain axis field in order to create effective therapies for AD. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease.

Author

Rajani, Rikesh M., Ellingford, Robert, Hellmuth, Mariam, Harris, Samuel S., Taso, Orjona S., Graykowski, David, Lam, Francesca Kar Wey, Arber, Charles, Fertan, Emre, Danial, John S. H., Swire, Matthew, Lloyd, Marcus, Giovannucci, Tatiana A., Bourdenx, Mathieu, Klenerman, David, Vassar, Robert, Wray, Selina, Sala Frigerio, Carlo, and Busche, Marc Aurel

Subjects
ALZHEIMER'S disease, AMYLOID, OLIGODENDROGLIA, BRAIN diseases, LABORATORY mice
Abstract

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD. Neurons are thought to be the primary source of pathogenic amyloid beta (Aβ) in Alzheimer's disease. This study identifies oligodendrocytes as significant contributors to Aβ production and shows that suppressing Aβ in oligodendrocytes rescues early neuronal dysfunction in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Oligodendrocytes and neurons contribute to amyloid-β deposition in Alzheimer’s disease

Author

Sasmita, Andrew Octavian, primary, Depp, Constanze, additional, Nazarenko, Taisiia, additional, Sun, Ting, additional, Siems, Sophie B., additional, Yu, Xuan, additional, Boehler, Carolin, additional, Ong, Erinne Cherisse, additional, Bues, Bastian, additional, Evangelista, Lisa, additional, Morgado, Barbara, additional, Wu, Zoe, additional, Ruhwedel, Torben, additional, Subramanian, Swati, additional, Börensen, Friederike, additional, Overhoff, Katharina, additional, Spieth, Lena, additional, Berghoff, Stefan A., additional, Sadleir, Katherine Rose, additional, Vassar, Robert, additional, Eggert, Simone, additional, Goebbels, Sandra, additional, Saito, Takashi, additional, Saido, Takaomi, additional, Möbius, Wiebke, additional, Castelo-Branco, Gonçalo, additional, Klafki, Hans-Wolfgang, additional, Wirths, Oliver, additional, Wiltfang, Jens, additional, Jäkel, Sarah, additional, Yan, Riqiang, additional, and Nave, Klaus-Armin, additional

Published
2023
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23. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease

Author

Hur, Ji-Yeun, Frost, Georgia R., Wu, Xianzhong, Crump, Christina, Pan, Si Jia, Wong, Eitan, Barros, Marilia, Li, Thomas, Nie, Pengju, Zhai, Yujia, Wang, Jen Chyong, TCW, Julia, Guo, Lei, McKenzie, Andrew, Ming, Chen, Zhou, Xianxiao, Wang, Minghui, Sagi, Yotam, Renton, Alan E., Esposito, Bianca T., Kim, Yong, Sadleir, Katherine R., Trinh, Ivy, Rissman, Robert A., Vassar, Robert, Zhang, Bin, Johnson, Douglas S., Masliah, Eliezer, Greengard, Paul, Goate, Alison, and Li, Yue-Ming

Published
2020
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25. Store depletion-induced h-channel plasticity rescues a channelopathy linked to Alzheimer’s disease

Author

Musial, Timothy F., Molina-Campos, Elizabeth, Bean, Linda A., Ybarra, Natividad, Borenstein, Ronen, Russo, Matthew L., Buss, Eric W., Justus, Daniel, Neuman, Krystina M., Ayala, Gelique D., Mullen, Sheila A., Voskobiynyk, Yuliya, Tulisiak, Christopher T., Fels, Jasmine A., Corbett, Nicola J., Carballo, Gabriel, Kennedy, Colette D., Popovic, Jelena, Ramos-Franco, Josefina, Fill, Michael, Pergande, Melissa R., Borgia, Jeffrey A., Corbett, Grant T., Pahan, Kalipada, Han, Ye, Chetkovich, Dane M., Vassar, Robert J., Byrne, Richard W., Matthew Oh, M., Stoub, Travis R., Remy, Stefan, Disterhoft, John F., and Nicholson, Daniel A.

Published
2018
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27. Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifiesLRRC4C, LHX5-AS1and nominates ancestry-specific lociPTPRK,GRB14, andKIAA0825as novel risk loci for Alzheimer’s disease: the Alzheimer’s Disease Genetics Consortium

Author

Rajabli, Farid, primary, Benchek, Penelope, additional, Tosto, Giuseppe, additional, Kushch, Nicholas, additional, Sha, Jin, additional, Bazemore, Katrina, additional, Zhu, Congcong, additional, Lee, Wan-Ping, additional, Haut, Jacob, additional, Hamilton-Nelson, Kara L., additional, Wheeler, Nicholas R., additional, Zhao, Yi, additional, Farrell, John J., additional, Grunin, Michelle A., additional, Leung, Yuk Yee, additional, Kuksa, Pavel P., additional, Li, Donghe, additional, Lucio da Fonseca, Eder, additional, Mez, Jesse B., additional, Palmer, Ellen L., additional, Pillai, Jagan, additional, Sherva, Richard M., additional, Song, Yeunjoo E., additional, Zhang, Xiaoling, additional, Iqbal, Taha, additional, Pathak, Omkar, additional, Valladares, Otto, additional, Kuzma, Amanda B., additional, Abner, Erin, additional, Adams, Perrie M., additional, Aguirre, Alyssa, additional, Albert, Marilyn S., additional, Albin, Roger L., additional, Allen, Mariet, additional, Alvarez, Lisa, additional, Apostolova, Liana G., additional, Arnold, Steven E., additional, Asthana, Sanjay, additional, Atwood, Craig S., additional, Ayres, Gayle, additional, Baldwin, Clinton T., additional, Barber, Robert C., additional, Barnes, Lisa L., additional, Barral, Sandra, additional, Beach, Thomas G., additional, Becker, James T., additional, Beecham, Gary W., additional, Beekly, Duane, additional, Benitez, Bruno A., additional, Bennett, David, additional, Bertelson, John, additional, Bird, Thomas D., additional, Blacker, Deborah, additional, Boeve, Bradley F., additional, Bowen, James D., additional, Boxer, Adam, additional, Brewer, James, additional, Burke, James R., additional, Burns, Jeffrey M., additional, Buxbaum, Joseph D., additional, Cairns, Nigel J., additional, Cantwell, Laura B., additional, Cao, Chuanhai, additional, Carlson, Christopher S., additional, Carlsson, Cynthia M., additional, Carney, Regina M., additional, Carrasquillo, Minerva M., additional, Chasse, Scott, additional, Chesselet, Marie-Francoise, additional, Chin, Nathaniel A., additional, Chui, Helena C., additional, Chung, Jaeyoon, additional, Craft, Suzanne, additional, Crane, Paul K., additional, Cribbs, David H., additional, Crocco, Elizabeth A., additional, Cruchaga, Carlos, additional, Cuccaro, Michael L., additional, Cullum, Munro, additional, Darby, Eveleen, additional, Davis, Barbara, additional, De Jager, Philip L., additional, DeCarli, Charles, additional, DeToledo, John, additional, Dick, Malcolm, additional, Dickson, Dennis W., additional, Dombroski, Beth A., additional, Doody, Rachelle S., additional, Duara, Ranjan, additional, Ertekin-Taner, NIlüfer, additional, Evans, Denis A., additional, Faber, Kelley M., additional, Fairchild, Thomas J., additional, Fallon, Kenneth B., additional, Fardo, David W., additional, Farlow, Martin R., additional, Fernandez-Hernandez, Victoria, additional, Ferris, Steven, additional, Foroud, Tatiana M., additional, Frosch, Matthew P., additional, Fulton-Howard, Brian, additional, Galasko, Douglas R., additional, Gamboa, Adriana, additional, Gearing, Marla, additional, Geschwind, Daniel H., additional, Ghetti, Bernardino, additional, Gilbert, John R., additional, Goate, Alison M., additional, Grabowski, Thomas J., additional, Graff-Radford, Neill R., additional, Green, Robert C., additional, Growdon, John H., additional, Hakonarson, Hakon, additional, Hall, James, additional, Hamilton, Ronald L., additional, Harari, Oscar, additional, Hardy, John, additional, Harrell, Lindy E., additional, Head, Elizabeth, additional, Henderson, Victor W., additional, Hernandez, Michelle, additional, Hohman, Timothy, additional, Honig, Lawrence S., additional, Huebinger, Ryan M., additional, Huentelman, Matthew J., additional, Hulette, Christine M., additional, Hyman, Bradley T., additional, Hynan, Linda S., additional, Ibanez, Laura, additional, Jarvik, Gail P., additional, Jayadev, Suman, additional, Jin, Lee-Way, additional, Johnson, Kim, additional, Johnson, Leigh, additional, Kamboh, M. Ilyas, additional, Karydas, Anna M., additional, Katz, Mindy J., additional, Kauwe, John S., additional, Kaye, Jeffrey A., additional, Keene, C. Dirk, additional, Khaleeq, Aisha, additional, Kim, Ronald, additional, Knebl, Janice, additional, Kowall, Neil W., additional, Kramer, Joel H., additional, Kukull, Walter A., additional, LaFerla, Frank M., additional, Lah, James J., additional, Larson, Eric B., additional, Lerner, Alan, additional, Leverenz, James B., additional, Levey, Allan I., additional, Lieberman, Andrew P., additional, Lipton, Richard B., additional, Logue, Mark, additional, Lopez, Oscar L., additional, Lunetta, Kathryn L., additional, Lyketsos, Constantine G., additional, Mains, Douglas, additional, Margaret, Flanagan E., additional, Marson, Daniel C., additional, Martin, Eden R R., additional, Martiniuk, Frank, additional, Mash, Deborah C., additional, Masliah, Eliezer, additional, Massman, Paul, additional, Masurkar, Arjun, additional, McCormick, Wayne C., additional, McCurry, Susan M., additional, McDavid, Andrew N., additional, McDonough, Stefan, additional, McKee, Ann C., additional, Mesulam, Marsel, additional, Miller, Bruce L., additional, Miller, Carol A., additional, Miller, Joshua W., additional, Montine, Thomas J., additional, Monuki, Edwin S., additional, Morris, John C., additional, Mukherjee, Shubhabrata, additional, Myers, Amanda J., additional, Nguyen, Trung, additional, O’Bryant, Sid, additional, Olichney, John M., additional, Ory, Marcia, additional, Palmer, Raymond, additional, Parisi, Joseph E., additional, Paulson, Henry L., additional, Pavlik, Valory, additional, Paydarfar, David, additional, Perez, Victoria, additional, Peskind, Elaine, additional, Petersen, Ronald C., additional, Pierce, Aimee, additional, Polk, Marsha, additional, Poon, Wayne W., additional, Potter, Huntington, additional, Qu, Liming, additional, Quiceno, Mary, additional, Quinn, Joseph F., additional, Raj, Ashok, additional, Raskind, Murray, additional, Reiman, Eric M., additional, Reisberg, Barry, additional, Reisch, Joan S., additional, Ringman, John M., additional, Roberson, Erik D., additional, Rodriguear, Monica, additional, Rogaeva, Ekaterina, additional, Rosen, Howard J., additional, Rosenberg, Roger N., additional, Royall, Donald R., additional, Sager, Mark A., additional, Sano, Mary, additional, Saykin, Andrew J., additional, Schneider, Julie A., additional, Schneider, Lon S., additional, Seeley, William W., additional, Slifer, Susan H., additional, Small, Scott, additional, Smith, Amanda G., additional, Smith, Janet P., additional, Sonnen, Joshua A., additional, Spina, Salvatore, additional, St George-Hyslop, Peter, additional, Stern, Robert A., additional, Stevens, Alan B., additional, Strittmatter, Stephen M., additional, Sultzer, David, additional, Swerdlow, Russell H., additional, Tanzi, Rudolph E., additional, Tilson, Jeffrey L., additional, Trojanowski, John Q., additional, Troncoso, Juan C., additional, Tsuang, Debby W., additional, Van Deerlin, Vivianna M., additional, van Eldik, Linda J., additional, Vance, Jeffery M., additional, Vardarajan, Badri N., additional, Vassar, Robert, additional, Vinters, Harry V., additional, Vonsattel, Jean-Paul, additional, Weintraub, Sandra, additional, Welsh-Bohmer, Kathleen A., additional, Whitehead, Patrice L., additional, Wijsman, Ellen M., additional, Wilhelmsen, Kirk C., additional, Williams, Benjamin, additional, Williamson, Jennifer, additional, Wilms, Henrik, additional, Wingo, Thomas S., additional, Wisniewski, Thomas, additional, Woltjer, Randall L., additional, Woon, Martin, additional, Wright, Clinton B., additional, Wu, Chuang-Kuo, additional, Younkin, Steven G., additional, Yu, Chang-En, additional, Yu, Lei, additional, Zhu, Xiongwei, additional, Kunkle, Brian W., additional, Bush, William S., additional, Wang, Li-San, additional, Farrer, Lindsay A., additional, Haines, Jonathan L., additional, Mayeux, Richard, additional, Pericak-Vance, Margaret A., additional, Schellenberg, Gerard D., additional, Jun, Gyungah R., additional, Reitz, Christiane, additional, and Naj, Adam C., additional

Published
2023
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30. β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE

Author

Vassar, Robert, Bennett, Brian D., Babu-Khan, Safura, Kahn, Steve, Mendiaz, Elizabeth A., Denis, Paul, Teplow, David B., Ross, Sandra, Amarante, Patricia, Loeloff, Richard, Luo, Yi, Fisher, Seth, Fuller, Janis, Edenson, Steven, Lile, Jackson, Jarosinski, Mark A., Biere, Anja Leona, Curran, Eileen, Burgess, Teresa, Louis, Jean-Claude, Collins, Frank, Treanor, James, Rogers, Gary, and Citron, Martin

Published
1999

33. A Furin-like Convertase Mediates Propeptide Cleavage of BACE, the Alzheimer's β-Secretase*

Author

Bennett, Brian D, Denis, Paul, Haniu, Mitsuru, Teplow, David B, Kahn, Steve, Louis, Jean-Claude, Citron, Martin, and Vassar, Robert

Subjects
Brain Disorders, Aging, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Acquired Cognitive Impairment, Dementia, 2.1 Biological and endogenous factors, Aetiology, Alzheimer Disease, Amino Acid Sequence, Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases, Base Sequence, Catalysis, Cell Line, DNA Primers, Endopeptidases, Furin, Golgi Apparatus, Humans, Hydrolysis, Molecular Sequence Data, Recombinant Proteins, Subtilisins, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology
Abstract

The novel transmembrane aspartic protease BACE (for Beta-site APP Cleaving Enzyme) is the beta-secretase that cleaves amyloid precursor protein to initiate beta-amyloid formation. As such, BACE is a prime therapeutic target for the treatment of Alzheimer's disease. BACE, like other aspartic proteases, has a propeptide domain that is removed to form the mature enzyme. BACE propeptide cleavage occurs at the sequence RLPR downward arrowE, a potential furin recognition motif. Here, we explore the role of furin in BACE propeptide domain processing. BACE propeptide cleavage in cells does not appear to be autocatalytic, since an inactive D93A mutant of BACE is still cleaved appropriately. BACE and furin co-localize within the Golgi apparatus, and propeptide cleavage is inhibited by brefeldin A and monensin, drugs that disrupt trafficking through the Golgi. Treatment of cells with the calcium ionophore, leading to inhibition of calcium-dependent proteases including furin, or transfection with the alpha(1)-antitrypsin variant alpha(1)-PDX, a potent furin inhibitor, dramatically reduces cleavage of the BACE propeptide. Moreover, the BACE propeptide is not processed in the furin-deficient LoVo cell line; however, processing is restored upon furin transfection. Finally, in vitro digestion of recombinant soluble BACE with recombinant furin results in complete cleavage only at the established E46 site. Taken together, our results strongly suggest that furin, or a furin-like proprotein convertase, is responsible for cleaving the BACE propeptide domain to form the mature enzyme.

Published
2000

36. Death induced by survival gene elimination (DISE) contributes to neurotoxicity in Alzheimer’s disease

Author

Paudel, Bidur, primary, Jeong, Si-Yeon, additional, Martinez, Carolina Pena, additional, Rickman, Alexis, additional, Haluck-Kangas, Ashley, additional, Bartom, Elizabeth T., additional, Fredriksen, Kristina, additional, Affaneh, Amira, additional, Kessler, John A., additional, Mazzulli, Joseph R., additional, Murmann, Andrea E., additional, Rogalski, Emily, additional, Geula, Changiz, additional, Ferreira, Adriana, additional, Heckmann, Bradlee L., additional, Green, Douglas R., additional, Sadleir, Katherine R., additional, Vassar, Robert, additional, and Peter, Marcus E., additional

Published
2022
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42. A conserved annexin A6–mediated membrane repair mechanism in muscle, heart, and nerve

Author

Demonbreun, Alexis R., primary, Bogdanovic, Elena, additional, Vaught, Lauren A., additional, Reiser, Nina L., additional, Fallon, Katherine S., additional, Long, Ashlee M., additional, Oosterbaan, Claire C., additional, Hadhazy, Michele, additional, Page, Patrick G.T., additional, Joseph, Prem Raj B., additional, Cowen, Gabrielle, additional, Telenson, Alexander M., additional, Khatri, Ammaarah, additional, Sadleir, Katherine R., additional, Vassar, Robert, additional, and McNally, Elizabeth M., additional

Published
2022
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43. Pyroglutamate-3 Amyloid-β Deposition in the Brains of Humans, Non-Human Primates, Canines, and Alzheimer Disease–Like Transgenic Mouse Models

Author

Frost, Jeffrey L., Le, Kevin X., Cynis, Holger, Ekpo, Elizabeth, Kleinschmidt, Martin, Palmour, Roberta M., Ervin, Frank R., Snigdha, Shikha, Cotman, Carl W., Saido, Takaomi C., Vassar, Robert J., George-Hyslop, Peter St., Ikezu, Tsuneya, Schilling, Stephan, Demuth, Hans-Ulrich, and Lemere, Cynthia A.

Published
2013
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45. Endothelial BACE1 Impairs Cerebral Small Vessels via Tight Junctions and eNOS

Author

Zhou, Haoyue, primary, Gao, Feng, additional, Yang, Xiaoli, additional, Lin, Tingting, additional, Li, Zhenxing, additional, Wang, Qiong, additional, Yao, Yang, additional, Li, Lei, additional, Ding, Xinxin, additional, Shi, Kaibin, additional, Liu, Qiang, additional, Bao, Hong, additional, Long, Zhenyu, additional, Wu, Zujun, additional, Vassar, Robert, additional, Cheng, Xin, additional, Li, Rena, additional, and Shen, Yong, additional

Published
2022
Full Text
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