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Genetic basis of cerebral amyloidosis
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.
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.