- Email: [email protected]
Immunotherapy, intra and intra-CNS actions
Alzheimer’s & Dementia 1 (Suppl 1) (2005)
ABSTRACTS SATURDAY, JUNE 18, 2005 CLINICAL TRIALS TEST THE “AMYLOID HYPOTHESIS:” TUTORIAL ON CURRENT APPROACHES AND THEIR MECHANISMS AM-01
GENETIC BASIS OF CEREBRAL AMYLOIDOSIS
Rudolph Tanzi; Harvard Medical School, Charlestown, MA, USA Alzheimer’s disease (AD is the most common form of dementia in the elderly and a genetically complex disease. While any of over 160 mutations in three genes (APP, PSEN1, PSEN2) cause the early-onset form of AD, the e4 variant of the gene encoding apolipoprotein E (APOE) increases susceptibility for late-onset (60) AD. Interestingly, all four of the established AD genes harbor gene defects that serve to increase the accumulation of the Ab peptide and b-amyloid in the brain. These findings have prompted clinical trials targeted at either curbing the production of, or promoting the clearance of Ab, using a variety of strategies. Meanwhile, roughly 70% of the genetic variance of AD is not explained by the four known genes, and numerous candidate genes have been proposed over the past decade. We have recently identified strong candidates for the AD including IDE, encoding insulin degrading enzyme gene on chromosome 10, and UBQLN1, encoding ubiquilin, on chromosome 9. Ultimately, the identification, validation, and characterization of novel AD genes should accelerate the means to better predict, diagnose, prevent and treat this devastating disease. AM-02
NATURAL HISTORY OF AMYLOID-BETA PEPTIDES IN THE CNS AND PERIPHERY
Steven Younkin; Mayo Clinic, Jacksonville, FL, USA Abstract not available. AM-03
OLIGOMERS/PROTOFIBRIALS/ADDLS
Grant Krafft; Acumen Pharmaceuticals, Glenview, IL, USA A major paradigm shift is underway in the quest to understand, treat and prevent Alzheimer’s disease (AD). The prevailing “amyloid cascade” hypothesis of the early 1990s invoked amyloid deposition as the cause of AD, but growing evidence now suggests that neither amyloid plaques nor the other AD hallmark, neurofibrillary tangles, cause or propagate the disease. Instead, soluble, globular assemblies of the A 1-42 peptide known as ADDLs (amyloid -derived diffusible ligands), discovered in 1995, are emerging as the likely AD molecular pathogens. ADDLs are the neurotoxic subset of A 1-42 assemblies capable of blocking learning and memory. ADDLs are substantially elevated in AD brain tissue and cerebrospinal fluid, and they have been shown to block the maintenance of long term potentiation in brain slice cultures and when injected directly into rat brains. ADDLs exhibit selective neurotoxicity to neurons in the CA1 hippocampal region, and recently, they have been shown to bind directly to post-synaptic dendritic spines. An immediate consequence of ADDL binding is the rapid, local synaptic upregulation of the immediate early gene Arc, and it has been suggested that dysregulation of Arc leads to LTP failure. Many details surrounding the abnormal neuronal signaling triggered by ADDLs remain to be elucidated, however, our current level of understanding of ADDL formation, structure and activity provides the
foundation for drug discovery activities that will generate anti-ADDL therapeutics for human clinical studies over the next several years. AM-04
AMYLOID IMMUNOTHERAPY, EXTRA-CNS ACTIONS
David Holtzman; Washington University, St. Louis, MO, USA Background: Aggregation of the normally soluble amyloid- (A) peptide in the brain is important in the pathogenesis of Alzheimer’s disease (AD). Degradation and transport of A are critical processes that regulate whether or not A will aggregate. Data suggests that A is actively and passively transported between the brain and the blood. Objective(s): The effects of active immunization with A appear to be mediated by anti-A antibodies. Utilizing antibodies that recognize soluble forms of A, we have asked whether these antibodies can be useful in further understanding the relationship between A metabolism between the brain and the blood. Methods and Results: Antibodies that recognize soluble A have been peripherally administered to animal models that develop A-related pathology in the brain that are similar to changes seen in AD (e.g. PDAPP mice). These studies have revealed that a large percentage of A that is produced in the brain is cleared into the blood. Further, such antibodies have been shown to prevent influx of A from the blood to the brain. One monoclonal antibody to soluble A (m266) has been shown to decrease brain A deposition when peripherally administered beginning at a young age (prior to plaque formation). In addition, administration of m266 was shown to rapidly improve function in certain cognitive tasks and that this rapid improvement was independent of plaque removal. Administration of m266 to PDAPP transgenic mice results in a rapid and large increase in plasma A that is derived from the brain over hours. Assessment of plasma A following peripheral m266 administration is able to reveal a strong correlation with levels of A deposition in the brain. Conclusions: Use of antibodies to soluble A have assisted in revealing that a large amount of A produced in the brain is normally cleared into the blood and that A in the brain and blood are in equilibrium. Effects of antibodies to soluble A suggest that some effects of anti-A antibodies may be via modulation of this equilibrium. Such antibodies may be useful as therapeutics as well as in development of better peripheral biomarkers of A deposition/plaque load in the brain. AM-05
IMMUNOTHERAPY, INTRA AND INTRA-CNS ACTIONS
Frank L. Heppner; Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland Background: Schenk et al. provided the first evidence that immunization of A plaque-forming transgenic mice with aggregated synthetic A can diminish or prevent brain A accumulation. Objective: The mechanism of plaque clearance upon A vaccination, however, remains ill-defined. Presently, various hypotheses exist: on the one hand, anti-A antibodies may induce a change in the equilibrium of A between the central nervous system (CNS) and plasma and might reduce brain A burden, at least in part, by altering CNS and plasma A clearance by acting as a peripheral “sink”. Alternatively (or additionally), immunotherapy may act exclusively within the CNS. To this end, microglial cells were described to be a key
1552-5260/05/$ – see front matter © 2005 The Alzheimer’s Association. All rights reserved.
S2
Abstracts: Amyloid Pre-conference / 1 (Suppl 1) (2005)
player in lowering plaque load in an ex vivo assay: immune IgG-decorated amyloid plaques triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis. Microglial activation was also shown to accompany the anti-A-antibody mediated decrease in A in an in vivo imaging study. Methods: To learn whether microglial cells are crucial for lowering A burden upon vaccination in vivo, we are presently crossbreeding A plaque-forming transgenic mice with CD11b-HSVTK mice which allow an inducible paralysis of microglial cells at given time points. Conclusions: Tackling A by means of vaccination appears to be a feasible approach for preventing or even treating AD. However, it will be crucial to understand the exact mechanism of anti-A antibody-mediated A decrease in order to (i) design efficient anti-AD drugs and (ii) to circumvent detrimental side effects.
113,818 improved spatial learning, which correlated with decreased A. In non-transgenic animals, the levels of APP C-terminal fragments and secreted APP were reduced by the ACAT inhibitor, suggesting that CP113,818 treatment also regulates processing of endogenous APP. We have recently found that a different ACAT inhibitor, CI-1011 or avasimibe, also reduces A generation in cell-based assays. Interestingly, CI-1011 was effective in reducing brain cholesteryl-esters in mice. CI-1011 has previously reached phase III trials for prevention of atherosclerosis. The potential of statins and ACAT inhibitors as novel strategies for the treatment and prevention of Alzheimer’s disease will be discussed. AM-08
ALPHA SECRETASE
Joseph Buxbaum; Mt. Sinai School of Medicine, New York, NY, USA AM-06
FUNCTIONAL GAG MIMETICS AS AN APPROACH FOR THE TREATMENT OF AMYLOID DISEASES
Patrick Tremblay1, Paul Aisen2, Denis Garceau1; 1Neurochem, Inc., Laval, Province of Quebec, Canada; 2Georgetown University Medical Center, Washington, D.C., USA Background: The ABeta peptide is the main constituent of senile plaques present in the brain of patients with Alzheimer’s disease (AD) and is believed to be implicated directly in the neurodegenerative process. Glycosaminoglycans (GAGs) contribute to the amyloidogenic cascade by promoting the fibrillogenic process that leads to plaque formation. Objective(s): As a therapeutic approach to AD, we developed a series of functional low-molecular weight anionic GAG-mimetic compounds designed to bind to soluble ABeta peptides and facilitate their clearance. Methods: Treatment of hAPP transgenic mice (TgCRND8) with the GAG-mimetic compound, 3-amino-1-propanesulfonic acid (3APS), has been found to reduce both cerebral ABeta40/42 levels and amyloid deposits. Moreover, 3APS has been shown to be safe and well tolerated in human subjects. In a 3-month randomized, double-blind, placebo-controlled Phase II study with mild-to-moderate AD patients, 3APS treatment resulted in a significant dose-dependent reduction of cerebrospinal fluid (CSF) ABeta42 levels. This pharmacological effect was greater in mild than in moderate AD subjects. The open-label extension of the Phase II study revealed that a majority of the patients with mild AD presented stable or improved ADAScog scores over 28 months. Conclusions: Altogether, these results support the anti-amyloid activity of 3APS and underline its potential diseasemodifying activity. We propose that 3APS represents a new and promising therapeutic class of compounds for the treatment of AD. AM-07
MODIFIERS OF CHOLESTEROL METABOLISM
Dora M. Kovacs; Massachusetts General Hospital / Harvard Medical School, Charlestown (Boston), MA, USA A generation is strongly regulated by cellular cholesterol levels. Statins and other therapies already developed for dyslipidemia and atherosclerosis are gaining attention as attractive strategies for also reducing amyloid pathology. Statins appear effective in lowering both cholesterol and A generation in cellular and animal models of AD. Results from the first prospective clinical trials offer hope that simvastatin and atorvastatin may stabilize cognitive function in AD patients. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, which convert cholesterol and fatty acids into cholesteryl-esters, are currently being developed for treatment of cardiovascular disease. A well-characterized ACAT inhibitor, CP-113,818, reduces secreted A levels in cellular models of AD by inhibiting amyloidogenic processing of APP (Puglielli et al., 2001). We have also found that CP-113,818 ameliorates AD-like pathology in the brains of transgenic mice expressing human APP751 containing the London (V717I) and Swedish (K670M/N671L) mutations (Hutter-Paier et al., 2004). In this study, two months of treatment with CP-113,818 markedly decreased brain and liver cholesteryl-esters, while also preventing brain amyloid accumulation as assessed by immunostaining and ELISA assays. Additionally, CP-
Studies in post-mortem samples have demonstrated that the levels of Abeta in the brain correlate with dementia, indicating that agents that regulate the formation, deposition, and/or clearance of Abeta may be therapeutic targets in Alzheimer’s disease. Fifteen years ago, it was shown that the cleavage of APP by alpha-secretase was regulated by agents that activate protein kinase C. Alpha-secretase cleavage of APP led to release of the large extracellular domain and the accumulation of a cytoplasmic fragment in the cells. It was later shown that, with activation of alpha-secretase, there was a reduction in the amount of Abeta formed. These studies were extended to show that physiological compounds that activate protein kinase C, such as cholinergic agonist, also have the same effect. Over this period, the identity of alpha-secretase was unknown. However, in 1998 and 1999, regulated and constitutive alpha-secretases were identified as TACE/ADAM17 and kuzbanian/ADAM10. It has also now shown that the activation of protein kinase C in vivo also activates APP processing. For example, compounds such as the anti-Parkinson’s drug, rasagiline, are able to regulate APP processing and Abeta formation in vivo. Similarly, over expression of ADAM10 has been shown to regulate APP processing in vivo and decrease plaque formation in a mouse model. Inhibiting endogenous ADAM10 had the reverse effect. Alpha-secretase can therefore be considered a therapeutic target and it is important to ask what is the function of this protein and of the alpha-cleavage of APP. Studies showed that alpha-secretase had multiple targets and the disruption of alpha-secretases led to death in mouse models. One interesting effect of the cleavage of APP by alphasecretases is that this leads to gamma-cleavage of APP, which releases a cytoplasmic fragment of APP that can function in cytoplasmic and nuclear signaling. This signaling appears to involve proteins that bind APP, such as FE65, and there is evidence that APP/FE65 can regulate gene expression. It is not yet known which genes might be regulated by APP/FE65, however, some of our recent studies indicate that a unique transcription factor interacts with APP/FE65, regulating the expression of downstream targets. AM-09
PRESENILIN/GAMMA SECRETASE AS A THERAPEUTIC TARGET
Michael S. Wolfe; Brigham & Women’s Hospital, Boston, MA, USA Gamma-secretase catalyzes proteolysis within cell membranes as the last step in the formation of amyloid-beta from its precursor protein (APP). This protease is comprised of four different membrane proteins, with presenilin as the catalytic component. Small molecule probes have been essential for characterizing and identifying this enzyme as well as advancing the understanding of its catalytic mechanism. Gamma-secretase also cleaves other membrane proteins besides APP, the most notorious being the Notch receptor. Because Notch signaling is critical for cell differentiation, gamma-secretase inhibitors that block both APP and Notch proteolysis can cause severe toxicities by interfering with essential processes such as hematopoiesis. However, the recent identification of compounds that modulate the gamma-secretase complex to reduce amyloid-beta without affecting Notch signaling have renewed hope in this protease as a therapeutic target.
ABSTRACTS SATURDAY, JUNE 18, 2005 CLINICAL TRIALS TEST THE “AMYLOID HYPOTHESIS:” TUTORIAL ON CURRENT APPROACHES AND THEIR MECHANISMS AM-01
GENETIC BASIS OF CEREBRAL AMYLOIDOSIS
Rudolph Tanzi; Harvard Medical School, Charlestown, MA, USA Alzheimer’s disease (AD is the most common form of dementia in the elderly and a genetically complex disease. While any of over 160 mutations in three genes (APP, PSEN1, PSEN2) cause the early-onset form of AD, the e4 variant of the gene encoding apolipoprotein E (APOE) increases susceptibility for late-onset (60) AD. Interestingly, all four of the established AD genes harbor gene defects that serve to increase the accumulation of the Ab peptide and b-amyloid in the brain. These findings have prompted clinical trials targeted at either curbing the production of, or promoting the clearance of Ab, using a variety of strategies. Meanwhile, roughly 70% of the genetic variance of AD is not explained by the four known genes, and numerous candidate genes have been proposed over the past decade. We have recently identified strong candidates for the AD including IDE, encoding insulin degrading enzyme gene on chromosome 10, and UBQLN1, encoding ubiquilin, on chromosome 9. Ultimately, the identification, validation, and characterization of novel AD genes should accelerate the means to better predict, diagnose, prevent and treat this devastating disease. AM-02
NATURAL HISTORY OF AMYLOID-BETA PEPTIDES IN THE CNS AND PERIPHERY
Steven Younkin; Mayo Clinic, Jacksonville, FL, USA Abstract not available. AM-03
OLIGOMERS/PROTOFIBRIALS/ADDLS
Grant Krafft; Acumen Pharmaceuticals, Glenview, IL, USA A major paradigm shift is underway in the quest to understand, treat and prevent Alzheimer’s disease (AD). The prevailing “amyloid cascade” hypothesis of the early 1990s invoked amyloid deposition as the cause of AD, but growing evidence now suggests that neither amyloid plaques nor the other AD hallmark, neurofibrillary tangles, cause or propagate the disease. Instead, soluble, globular assemblies of the A 1-42 peptide known as ADDLs (amyloid -derived diffusible ligands), discovered in 1995, are emerging as the likely AD molecular pathogens. ADDLs are the neurotoxic subset of A 1-42 assemblies capable of blocking learning and memory. ADDLs are substantially elevated in AD brain tissue and cerebrospinal fluid, and they have been shown to block the maintenance of long term potentiation in brain slice cultures and when injected directly into rat brains. ADDLs exhibit selective neurotoxicity to neurons in the CA1 hippocampal region, and recently, they have been shown to bind directly to post-synaptic dendritic spines. An immediate consequence of ADDL binding is the rapid, local synaptic upregulation of the immediate early gene Arc, and it has been suggested that dysregulation of Arc leads to LTP failure. Many details surrounding the abnormal neuronal signaling triggered by ADDLs remain to be elucidated, however, our current level of understanding of ADDL formation, structure and activity provides the
foundation for drug discovery activities that will generate anti-ADDL therapeutics for human clinical studies over the next several years. AM-04
AMYLOID IMMUNOTHERAPY, EXTRA-CNS ACTIONS
David Holtzman; Washington University, St. Louis, MO, USA Background: Aggregation of the normally soluble amyloid- (A) peptide in the brain is important in the pathogenesis of Alzheimer’s disease (AD). Degradation and transport of A are critical processes that regulate whether or not A will aggregate. Data suggests that A is actively and passively transported between the brain and the blood. Objective(s): The effects of active immunization with A appear to be mediated by anti-A antibodies. Utilizing antibodies that recognize soluble forms of A, we have asked whether these antibodies can be useful in further understanding the relationship between A metabolism between the brain and the blood. Methods and Results: Antibodies that recognize soluble A have been peripherally administered to animal models that develop A-related pathology in the brain that are similar to changes seen in AD (e.g. PDAPP mice). These studies have revealed that a large percentage of A that is produced in the brain is cleared into the blood. Further, such antibodies have been shown to prevent influx of A from the blood to the brain. One monoclonal antibody to soluble A (m266) has been shown to decrease brain A deposition when peripherally administered beginning at a young age (prior to plaque formation). In addition, administration of m266 was shown to rapidly improve function in certain cognitive tasks and that this rapid improvement was independent of plaque removal. Administration of m266 to PDAPP transgenic mice results in a rapid and large increase in plasma A that is derived from the brain over hours. Assessment of plasma A following peripheral m266 administration is able to reveal a strong correlation with levels of A deposition in the brain. Conclusions: Use of antibodies to soluble A have assisted in revealing that a large amount of A produced in the brain is normally cleared into the blood and that A in the brain and blood are in equilibrium. Effects of antibodies to soluble A suggest that some effects of anti-A antibodies may be via modulation of this equilibrium. Such antibodies may be useful as therapeutics as well as in development of better peripheral biomarkers of A deposition/plaque load in the brain. AM-05
IMMUNOTHERAPY, INTRA AND INTRA-CNS ACTIONS
Frank L. Heppner; Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland Background: Schenk et al. provided the first evidence that immunization of A plaque-forming transgenic mice with aggregated synthetic A can diminish or prevent brain A accumulation. Objective: The mechanism of plaque clearance upon A vaccination, however, remains ill-defined. Presently, various hypotheses exist: on the one hand, anti-A antibodies may induce a change in the equilibrium of A between the central nervous system (CNS) and plasma and might reduce brain A burden, at least in part, by altering CNS and plasma A clearance by acting as a peripheral “sink”. Alternatively (or additionally), immunotherapy may act exclusively within the CNS. To this end, microglial cells were described to be a key
1552-5260/05/$ – see front matter © 2005 The Alzheimer’s Association. All rights reserved.
S2
Abstracts: Amyloid Pre-conference / 1 (Suppl 1) (2005)
player in lowering plaque load in an ex vivo assay: immune IgG-decorated amyloid plaques triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis. Microglial activation was also shown to accompany the anti-A-antibody mediated decrease in A in an in vivo imaging study. Methods: To learn whether microglial cells are crucial for lowering A burden upon vaccination in vivo, we are presently crossbreeding A plaque-forming transgenic mice with CD11b-HSVTK mice which allow an inducible paralysis of microglial cells at given time points. Conclusions: Tackling A by means of vaccination appears to be a feasible approach for preventing or even treating AD. However, it will be crucial to understand the exact mechanism of anti-A antibody-mediated A decrease in order to (i) design efficient anti-AD drugs and (ii) to circumvent detrimental side effects.
113,818 improved spatial learning, which correlated with decreased A. In non-transgenic animals, the levels of APP C-terminal fragments and secreted APP were reduced by the ACAT inhibitor, suggesting that CP113,818 treatment also regulates processing of endogenous APP. We have recently found that a different ACAT inhibitor, CI-1011 or avasimibe, also reduces A generation in cell-based assays. Interestingly, CI-1011 was effective in reducing brain cholesteryl-esters in mice. CI-1011 has previously reached phase III trials for prevention of atherosclerosis. The potential of statins and ACAT inhibitors as novel strategies for the treatment and prevention of Alzheimer’s disease will be discussed. AM-08
ALPHA SECRETASE
Joseph Buxbaum; Mt. Sinai School of Medicine, New York, NY, USA AM-06
FUNCTIONAL GAG MIMETICS AS AN APPROACH FOR THE TREATMENT OF AMYLOID DISEASES
Patrick Tremblay1, Paul Aisen2, Denis Garceau1; 1Neurochem, Inc., Laval, Province of Quebec, Canada; 2Georgetown University Medical Center, Washington, D.C., USA Background: The ABeta peptide is the main constituent of senile plaques present in the brain of patients with Alzheimer’s disease (AD) and is believed to be implicated directly in the neurodegenerative process. Glycosaminoglycans (GAGs) contribute to the amyloidogenic cascade by promoting the fibrillogenic process that leads to plaque formation. Objective(s): As a therapeutic approach to AD, we developed a series of functional low-molecular weight anionic GAG-mimetic compounds designed to bind to soluble ABeta peptides and facilitate their clearance. Methods: Treatment of hAPP transgenic mice (TgCRND8) with the GAG-mimetic compound, 3-amino-1-propanesulfonic acid (3APS), has been found to reduce both cerebral ABeta40/42 levels and amyloid deposits. Moreover, 3APS has been shown to be safe and well tolerated in human subjects. In a 3-month randomized, double-blind, placebo-controlled Phase II study with mild-to-moderate AD patients, 3APS treatment resulted in a significant dose-dependent reduction of cerebrospinal fluid (CSF) ABeta42 levels. This pharmacological effect was greater in mild than in moderate AD subjects. The open-label extension of the Phase II study revealed that a majority of the patients with mild AD presented stable or improved ADAScog scores over 28 months. Conclusions: Altogether, these results support the anti-amyloid activity of 3APS and underline its potential diseasemodifying activity. We propose that 3APS represents a new and promising therapeutic class of compounds for the treatment of AD. AM-07
MODIFIERS OF CHOLESTEROL METABOLISM
Dora M. Kovacs; Massachusetts General Hospital / Harvard Medical School, Charlestown (Boston), MA, USA A generation is strongly regulated by cellular cholesterol levels. Statins and other therapies already developed for dyslipidemia and atherosclerosis are gaining attention as attractive strategies for also reducing amyloid pathology. Statins appear effective in lowering both cholesterol and A generation in cellular and animal models of AD. Results from the first prospective clinical trials offer hope that simvastatin and atorvastatin may stabilize cognitive function in AD patients. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, which convert cholesterol and fatty acids into cholesteryl-esters, are currently being developed for treatment of cardiovascular disease. A well-characterized ACAT inhibitor, CP-113,818, reduces secreted A levels in cellular models of AD by inhibiting amyloidogenic processing of APP (Puglielli et al., 2001). We have also found that CP-113,818 ameliorates AD-like pathology in the brains of transgenic mice expressing human APP751 containing the London (V717I) and Swedish (K670M/N671L) mutations (Hutter-Paier et al., 2004). In this study, two months of treatment with CP-113,818 markedly decreased brain and liver cholesteryl-esters, while also preventing brain amyloid accumulation as assessed by immunostaining and ELISA assays. Additionally, CP-
Studies in post-mortem samples have demonstrated that the levels of Abeta in the brain correlate with dementia, indicating that agents that regulate the formation, deposition, and/or clearance of Abeta may be therapeutic targets in Alzheimer’s disease. Fifteen years ago, it was shown that the cleavage of APP by alpha-secretase was regulated by agents that activate protein kinase C. Alpha-secretase cleavage of APP led to release of the large extracellular domain and the accumulation of a cytoplasmic fragment in the cells. It was later shown that, with activation of alpha-secretase, there was a reduction in the amount of Abeta formed. These studies were extended to show that physiological compounds that activate protein kinase C, such as cholinergic agonist, also have the same effect. Over this period, the identity of alpha-secretase was unknown. However, in 1998 and 1999, regulated and constitutive alpha-secretases were identified as TACE/ADAM17 and kuzbanian/ADAM10. It has also now shown that the activation of protein kinase C in vivo also activates APP processing. For example, compounds such as the anti-Parkinson’s drug, rasagiline, are able to regulate APP processing and Abeta formation in vivo. Similarly, over expression of ADAM10 has been shown to regulate APP processing in vivo and decrease plaque formation in a mouse model. Inhibiting endogenous ADAM10 had the reverse effect. Alpha-secretase can therefore be considered a therapeutic target and it is important to ask what is the function of this protein and of the alpha-cleavage of APP. Studies showed that alpha-secretase had multiple targets and the disruption of alpha-secretases led to death in mouse models. One interesting effect of the cleavage of APP by alphasecretases is that this leads to gamma-cleavage of APP, which releases a cytoplasmic fragment of APP that can function in cytoplasmic and nuclear signaling. This signaling appears to involve proteins that bind APP, such as FE65, and there is evidence that APP/FE65 can regulate gene expression. It is not yet known which genes might be regulated by APP/FE65, however, some of our recent studies indicate that a unique transcription factor interacts with APP/FE65, regulating the expression of downstream targets. AM-09
PRESENILIN/GAMMA SECRETASE AS A THERAPEUTIC TARGET
Michael S. Wolfe; Brigham & Women’s Hospital, Boston, MA, USA Gamma-secretase catalyzes proteolysis within cell membranes as the last step in the formation of amyloid-beta from its precursor protein (APP). This protease is comprised of four different membrane proteins, with presenilin as the catalytic component. Small molecule probes have been essential for characterizing and identifying this enzyme as well as advancing the understanding of its catalytic mechanism. Gamma-secretase also cleaves other membrane proteins besides APP, the most notorious being the Notch receptor. Because Notch signaling is critical for cell differentiation, gamma-secretase inhibitors that block both APP and Notch proteolysis can cause severe toxicities by interfering with essential processes such as hematopoiesis. However, the recent identification of compounds that modulate the gamma-secretase complex to reduce amyloid-beta without affecting Notch signaling have renewed hope in this protease as a therapeutic target.