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Anti-amyloid approaches to treating Alzheimer's disease
Symposium:
S8 SMOOTH MUSCLE CELL IS THE PRIMARY TAR1331VASCULAR GET OF EVENTS LEADING FROM NOTCH3 MUTATIONS TO CADASIL
Approaches
INHIBITORS: BENEFITS AND LIMITATIONS
Rachelle S Doody, Baylor College of Medicine, Houston, TX
Anne Joutel, Facultk de Me?decine LmiboisiPre EPI 99-21, Paris France; Arnaud Francois, Fridt!ric Andreux, Swam Gaulis, V&rie Domenga, Facult6 de Me!decine lmiboisi&e EPI 99-21, Paris France; FranCoise Chapon, CHRU Caen Laboratoire de Neuropaihologie, Caen France; Catherine Godfrain, Clinique St Luc Laboratoire de Neuropathologie, Bruelles Belgique; Elisabeth Toumier-Lasserve, H@ital Lm-iboisi&e Labormoire de Cytog&&ique /EPI 99-21, Paris France CADASIL, an autosomal dominant adult onset condition, is an increasingly recognized cause of stroke and dementia in humans. CADASIL is underlaid by an arteriopathy which affects mainly the small cerebral arteries and is characterized by major alterations of the vascular smooth muscle cells. We recently established that CADASIL is due to mutations in the Notch3 gene. Notch3 belongs to the highly conserved Notchninl2 genes family encoding for large single pass transmembrane receptors involved in cell fate specification. Patients carry highly stereotyped mutations leading to an odd number of cysteine residues within the EGF-like repeats of the Notch3 receptor extracellular domain. Function of Notch3 as well as the mechanisms leading from Notch3 mutations to CADASIL are yet unknown. Using in situ hybridization and immunohistochemistry on normal human adult tissues we established that Notch3 expression is expressed only in vascular smooth muscle cells. We also established that Notch3 undergoes a proteolytic cleavage leading to a 210~kDa fragment including the ectodomain and a 97-kDa fragment including the transmembrane and the cytosolic domains. Both cleavage products are associated to form a heterodimeric receptor at the cell surface. In CADASIL tissues, immunohistochemical and immunoblot analyses showed evidence of a dramatic and selective accumulation of the 210.kDa Notch3 cleavage product within the vasculature. Immunoelectron microscopy revealed that Notch3 accumulation takes place at the cytoplasmic membrane of vascular smooth muscie cells. Amount of Notch3 mRNA was essentially identical in CADASIL and control tissues. These data strongly suggest that CADASIL mutations impair the clearance of the Notch3 ectodomain from the cell surface. Altogether our data indicate that vascular smooth muscle cell is the primary target in the cascade of events leading from Notch3 mutation to the CADASIL arteriopathy.
Symposium:
1351CHOLINESTERASE
Therapeutic
Therapeutic Approaches
ON PHARMACOLOGIC MANAGEMENT OF 1341UPDATE IORAL DISTURBANCES IN ALZHEIMER’S DISEASE
BEHAV-
Jrffrrey L. Cummings, UCLA Alzheimer’s Disease Center, Los Angeles, CA Alzheimer’s disease (AD) is commonly associated with a variety of neuropsychiatric disturbances including delusions, hallucinations, anxiety, depression, apathy, initability, disinhibition, agitation, and aberrant motor behaviors such as rummaging, pacing, and wondering. These behavior disturbances are stressful to the patient, exaggerate the burden of caregivers and are common reasons for admission to extended care facilities. Appropriate treatment of these behavioral changes may improve patient quality of life, reduce caregiver stress, and delay nursing home placement. Relatively few double blind, placebo control trials of psychotrophic medications have been formed in patients with AD. A recent randomized, control trial demonstrated that respiridone, an atypical antipsychotic reduced psychosis and aggression in patients with AD. Similarly, a control trial using olanzapine also demonstrated a beneficial effect on psychosis and aggression. Haloperidol, when used as an active comperater in these atudieb also demonstrated efficacy in reducing agitation. Haloperidol had an adverse effect on cognition comparative to atypical antipsychotic agents. Antidepressants are commonly used for depression and agitation m patients with AD and selective serotonin reuptake inhibitors are the most popular agents most currently used. Agitation has been the subject of recent pharmacologic trials and has been shown to respond to atypical antipsychotics, conventional neuroleptics, antiepileptic drugs, and trezidone. Recently, it has been observed that cholinesterase inhibitors appear to have a beneficial affect on behavior. Reduction in apathy and reduced visual hallucinations have been observed most frequently and some patients exhibit diminished agitation, delusions, hallucinations, depression, anxiety, and aberrant motor behavior. Side effects most be carefully monitored when using psychopharmacologic agents in patients with AD, and agents should be introduced at low doses and increased gradually. Psychopharmacologic intervention is warranted when behavioral disturbances are distressing and unresponsive to environmental manipulations.
The theory that central cholinergic deficiency causes symptoms in Alzheimer’s disease (AD) arose from observations that cholinergic makers and cholinergic cells are reduced in AD brains. The theory has been tested by drug treatments that enhance acetylcholinesterase (Ach) production, or interfere with normal Ach degradation, or act as cholinergic muscarinic agonists for post-synaptic brain neurons. Of these strategies, cholinesterase inhibition has been the most successful in randomized, double-blind, placebo-controlled trials. Two or three agents are now available in most of the world, and others are expected to gain regulatory approval. Anti-dementia drugs must demonstrate benefits for drug-treated patients on psychoactive tests of cognition, as well as on independently-conducted patient assessments performed by a clinician, with or without input from someone who knows the patient well. Clinical trials have also employed outcome measures that assess non-cognitive behaviors and functional abilities. Although cholinesterase inhibitors have clearly demonstrated benefits, the “magnitude” of the benefits, the consistency of response across subjects, and the duration of benefits have all been questioned and are under study. Cholinesterase inhibitors have eased the burden of AD for patients and their families, yet they do not prevent or arrest the disease. Theories of AD pathogenesis that emphasize links between risk factors, biochemical processes, and the cellular pathology of AD continue to support a role for cholinesterase inhibitors, but they also point to a critical need for additional therapeutic strategies.
1361CLINICAL
REVIEW OF NON-CHOLINERGIC
THERAPIES
Kenneth Rockwood, Dalhousie University, Halifax, NS Canada This presentation ~111 provide an overview of clinical experience with non-cholinergic therapies for the treatment of Alzheimer’s disease, with a focus on recent developments. The overview will include the use of anti-coagulants, anti-hypertensives (calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors), anti-oxidants, estrogen, ginko biloba, prednisone, propentofylline, non-steroidal anti-inflammatory drugs, and lipid lowering agents. Methodological challenges to the testing of such approaches, specifically in the context of understanding disease modification, will be discussed. Specific attention will be paid in this regard to issues of design, controls, instrumentation, and effect size. This presentation will provide an overview of clinical experience with non-cholinergic therapies for the treatment of Alzheimer’s disease, with a focus on recent developments. The overview will include the use of anti-coagulants, anti-hypertensives (calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors). anti-oxidants, estrogen, ginko biloba, prednisone, propentofyiline, non-steroidal anti-inflammatory drugs, and lipid lowering agents. Methodological challenges to the testing of such approaches, specifically in the context of understanding disease modification, will be discussed. Specific attention will be paid in this regard to issues of design. controls, instrumentation. and effect size.
1371ANTI-AMYLOID DISEASE
APPROACHES
TO TREATING
ALZHEIMER’S
Steven T. DeKosky, University of Pittsburgh School of Medicine, Pittsburgh, PA Therapeutic strategies in AD include suppression of neurofibrillary tangles and amyloid (neuritic) plaques. Medications to address the problem of neurofibrillary tangles are not yet within our grasp. However our understanding of the metabolism, genetics, and pathophysiology of amyloid precursor protein (APP), has brought us to the point of developing strategies for decreasing deposition of amyloid plaques. Normal metabolism of APP is mediated by an as-yet-unidentified enzyme, alpha secretax, which prevents the formation of beta amyloid, since it cuts the APP molecule in the middle of the beta amyloid fragment. In AD, two other enzymes, betaand gamma-secretase, cut the molecule in two other places, yielding beta amyloid, which deposits in the neuropil and results in neuritic plaques. These enzymes are all present in normal brain, but very little beta amyloid is deposited in normal brain. Beta secretase has recently been identified. Gamma secretase is not identified, although it may be presenilin 1, a molecule that when mutated, produces autosomal dominant AD. Five potential anti-amyloid interventions are proposed for potential use. Inhibitors of beta and gamma secretase would suppress production of amyloidogenic fragments. Compounds that bind to soluble beta amyloid (matching the periodicity of the beta-pleated sheet) would prevent aggregation. Immunization of transgenic mice with beta amyloid might remove beta rimyloid from the brain as it is formed. Compounds that dissolve iibrillar aggregated beta amyloid are also a potential therapy. Finally, a&inflammatory therapies may minimize the destructive elements of the brain’s reaction to beta amyloid aggregation.
S8 SMOOTH MUSCLE CELL IS THE PRIMARY TAR1331VASCULAR GET OF EVENTS LEADING FROM NOTCH3 MUTATIONS TO CADASIL
Approaches
INHIBITORS: BENEFITS AND LIMITATIONS
Rachelle S Doody, Baylor College of Medicine, Houston, TX
Anne Joutel, Facultk de Me?decine LmiboisiPre EPI 99-21, Paris France; Arnaud Francois, Fridt!ric Andreux, Swam Gaulis, V&rie Domenga, Facult6 de Me!decine lmiboisi&e EPI 99-21, Paris France; FranCoise Chapon, CHRU Caen Laboratoire de Neuropaihologie, Caen France; Catherine Godfrain, Clinique St Luc Laboratoire de Neuropathologie, Bruelles Belgique; Elisabeth Toumier-Lasserve, H@ital Lm-iboisi&e Labormoire de Cytog&&ique /EPI 99-21, Paris France CADASIL, an autosomal dominant adult onset condition, is an increasingly recognized cause of stroke and dementia in humans. CADASIL is underlaid by an arteriopathy which affects mainly the small cerebral arteries and is characterized by major alterations of the vascular smooth muscle cells. We recently established that CADASIL is due to mutations in the Notch3 gene. Notch3 belongs to the highly conserved Notchninl2 genes family encoding for large single pass transmembrane receptors involved in cell fate specification. Patients carry highly stereotyped mutations leading to an odd number of cysteine residues within the EGF-like repeats of the Notch3 receptor extracellular domain. Function of Notch3 as well as the mechanisms leading from Notch3 mutations to CADASIL are yet unknown. Using in situ hybridization and immunohistochemistry on normal human adult tissues we established that Notch3 expression is expressed only in vascular smooth muscle cells. We also established that Notch3 undergoes a proteolytic cleavage leading to a 210~kDa fragment including the ectodomain and a 97-kDa fragment including the transmembrane and the cytosolic domains. Both cleavage products are associated to form a heterodimeric receptor at the cell surface. In CADASIL tissues, immunohistochemical and immunoblot analyses showed evidence of a dramatic and selective accumulation of the 210.kDa Notch3 cleavage product within the vasculature. Immunoelectron microscopy revealed that Notch3 accumulation takes place at the cytoplasmic membrane of vascular smooth muscie cells. Amount of Notch3 mRNA was essentially identical in CADASIL and control tissues. These data strongly suggest that CADASIL mutations impair the clearance of the Notch3 ectodomain from the cell surface. Altogether our data indicate that vascular smooth muscle cell is the primary target in the cascade of events leading from Notch3 mutation to the CADASIL arteriopathy.
Symposium:
1351CHOLINESTERASE
Therapeutic
Therapeutic Approaches
ON PHARMACOLOGIC MANAGEMENT OF 1341UPDATE IORAL DISTURBANCES IN ALZHEIMER’S DISEASE
BEHAV-
Jrffrrey L. Cummings, UCLA Alzheimer’s Disease Center, Los Angeles, CA Alzheimer’s disease (AD) is commonly associated with a variety of neuropsychiatric disturbances including delusions, hallucinations, anxiety, depression, apathy, initability, disinhibition, agitation, and aberrant motor behaviors such as rummaging, pacing, and wondering. These behavior disturbances are stressful to the patient, exaggerate the burden of caregivers and are common reasons for admission to extended care facilities. Appropriate treatment of these behavioral changes may improve patient quality of life, reduce caregiver stress, and delay nursing home placement. Relatively few double blind, placebo control trials of psychotrophic medications have been formed in patients with AD. A recent randomized, control trial demonstrated that respiridone, an atypical antipsychotic reduced psychosis and aggression in patients with AD. Similarly, a control trial using olanzapine also demonstrated a beneficial effect on psychosis and aggression. Haloperidol, when used as an active comperater in these atudieb also demonstrated efficacy in reducing agitation. Haloperidol had an adverse effect on cognition comparative to atypical antipsychotic agents. Antidepressants are commonly used for depression and agitation m patients with AD and selective serotonin reuptake inhibitors are the most popular agents most currently used. Agitation has been the subject of recent pharmacologic trials and has been shown to respond to atypical antipsychotics, conventional neuroleptics, antiepileptic drugs, and trezidone. Recently, it has been observed that cholinesterase inhibitors appear to have a beneficial affect on behavior. Reduction in apathy and reduced visual hallucinations have been observed most frequently and some patients exhibit diminished agitation, delusions, hallucinations, depression, anxiety, and aberrant motor behavior. Side effects most be carefully monitored when using psychopharmacologic agents in patients with AD, and agents should be introduced at low doses and increased gradually. Psychopharmacologic intervention is warranted when behavioral disturbances are distressing and unresponsive to environmental manipulations.
The theory that central cholinergic deficiency causes symptoms in Alzheimer’s disease (AD) arose from observations that cholinergic makers and cholinergic cells are reduced in AD brains. The theory has been tested by drug treatments that enhance acetylcholinesterase (Ach) production, or interfere with normal Ach degradation, or act as cholinergic muscarinic agonists for post-synaptic brain neurons. Of these strategies, cholinesterase inhibition has been the most successful in randomized, double-blind, placebo-controlled trials. Two or three agents are now available in most of the world, and others are expected to gain regulatory approval. Anti-dementia drugs must demonstrate benefits for drug-treated patients on psychoactive tests of cognition, as well as on independently-conducted patient assessments performed by a clinician, with or without input from someone who knows the patient well. Clinical trials have also employed outcome measures that assess non-cognitive behaviors and functional abilities. Although cholinesterase inhibitors have clearly demonstrated benefits, the “magnitude” of the benefits, the consistency of response across subjects, and the duration of benefits have all been questioned and are under study. Cholinesterase inhibitors have eased the burden of AD for patients and their families, yet they do not prevent or arrest the disease. Theories of AD pathogenesis that emphasize links between risk factors, biochemical processes, and the cellular pathology of AD continue to support a role for cholinesterase inhibitors, but they also point to a critical need for additional therapeutic strategies.
1361CLINICAL
REVIEW OF NON-CHOLINERGIC
THERAPIES
Kenneth Rockwood, Dalhousie University, Halifax, NS Canada This presentation ~111 provide an overview of clinical experience with non-cholinergic therapies for the treatment of Alzheimer’s disease, with a focus on recent developments. The overview will include the use of anti-coagulants, anti-hypertensives (calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors), anti-oxidants, estrogen, ginko biloba, prednisone, propentofylline, non-steroidal anti-inflammatory drugs, and lipid lowering agents. Methodological challenges to the testing of such approaches, specifically in the context of understanding disease modification, will be discussed. Specific attention will be paid in this regard to issues of design, controls, instrumentation, and effect size. This presentation will provide an overview of clinical experience with non-cholinergic therapies for the treatment of Alzheimer’s disease, with a focus on recent developments. The overview will include the use of anti-coagulants, anti-hypertensives (calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors). anti-oxidants, estrogen, ginko biloba, prednisone, propentofyiline, non-steroidal anti-inflammatory drugs, and lipid lowering agents. Methodological challenges to the testing of such approaches, specifically in the context of understanding disease modification, will be discussed. Specific attention will be paid in this regard to issues of design. controls, instrumentation. and effect size.
1371ANTI-AMYLOID DISEASE
APPROACHES
TO TREATING
ALZHEIMER’S
Steven T. DeKosky, University of Pittsburgh School of Medicine, Pittsburgh, PA Therapeutic strategies in AD include suppression of neurofibrillary tangles and amyloid (neuritic) plaques. Medications to address the problem of neurofibrillary tangles are not yet within our grasp. However our understanding of the metabolism, genetics, and pathophysiology of amyloid precursor protein (APP), has brought us to the point of developing strategies for decreasing deposition of amyloid plaques. Normal metabolism of APP is mediated by an as-yet-unidentified enzyme, alpha secretax, which prevents the formation of beta amyloid, since it cuts the APP molecule in the middle of the beta amyloid fragment. In AD, two other enzymes, betaand gamma-secretase, cut the molecule in two other places, yielding beta amyloid, which deposits in the neuropil and results in neuritic plaques. These enzymes are all present in normal brain, but very little beta amyloid is deposited in normal brain. Beta secretase has recently been identified. Gamma secretase is not identified, although it may be presenilin 1, a molecule that when mutated, produces autosomal dominant AD. Five potential anti-amyloid interventions are proposed for potential use. Inhibitors of beta and gamma secretase would suppress production of amyloidogenic fragments. Compounds that bind to soluble beta amyloid (matching the periodicity of the beta-pleated sheet) would prevent aggregation. Immunization of transgenic mice with beta amyloid might remove beta rimyloid from the brain as it is formed. Compounds that dissolve iibrillar aggregated beta amyloid are also a potential therapy. Finally, a&inflammatory therapies may minimize the destructive elements of the brain’s reaction to beta amyloid aggregation.