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Amyloid-beta: From physiology to pathology
S4
Abstracts
SY1-A2-1 Alzheimer disease: From basic study to disease-modifying therapy Takeshi Iwatsubo Dept. Neuropathology, Univ. of Tokyo, Tokyo, Japan ␥-Secretase is a unique aspartic protease involved in intramembrane proteolysis of a set of membrane proteins including APP and Notch. The complex intramembrane structure of ␥-secretase hampered analysis of the mechanisms whereby hydrolysis of transmembrane (TM) substrates is executed within the lipid bilayer. We applied the substituted cysteine accessibility method to examine the structure of PS1 and showed that multiple TM domains (TMD) of PS1 contribute to the formation of a hydrophilic pore within the membrane. Some residues in TMD6, 7, PAL motif, TMD9 and TMD1 are predicted to form a subsite as judged by the pattern of competition of labeling by ␥-secretase inhibitors. Combination of molecular biological and chemical biological approaches will facilitate the understanding of the mechanism of intramembrane cleavage and the development of compounds that selectively inhibit A production. For the clinical development of disease-modifying drugs for Alzheimer disease, establishment of surrogate markers that represent AD pathology is mandatory. Current status of the clinical studies, i.e., ADNI/J-ADNI, will also be discussed. doi:10.1016/j.neures.2009.09.1482
SY1-A2-2 A plaque formation and associated neuritic pathology: Sequence of pathogenic events. Melanie Meyer-Luehmann Adolf-Butenandt Institute, Ludwig-Maximilians-University Munich, Germany Accumulation of amyloid-beta (A) is a neuropathological hallmark of Alzheimer’s disease, which contributes to alterations in neuronal structure and function. However, it is unclear what initiates plaque formation and whether it precedes the changes in neuritic architecture. We performed in vivo multiphoton imaging in APP transgenic mice and found, that plaques form quickly over 24 hours followed by neuritic changes, suggesting that these neuritic changes are a direct consequence of plaque formation. In another experiment, we used a novel in vivo optical reporter and examined the impact of A deposits on neural system function. In APP transgenic mice, neurons and dendritic segments close to plaques (compared to farther away) showed diminished baseline neuronal activity. In contrast to wild type mice, probe response near plaques was not increased by environmental stimuli. These data support the idea that plaques focally impair neural system function. doi:10.1016/j.neures.2009.09.1483
SY1-A2-3 Amyloid-beta: From physiology to pathology Ottavio Arancio Columbia University Medical Center, USA Amyloid- (A) is produced in large amounts in Alzheimer’s disease (AD). We have examined whether and how A interferes with both hippocampal memory and longterm potentiation (LTP), a cellular model of learning and memory. We found that nanomolar levels of A42 impair LTP and both spatial and fear memory through CREB down-regulation. The effects of A, however, are not limited to disruption of synaptic function and memory. In contrast to nanomolar concentrations, low picomolar A42 increases LTP and both spatial and contextual fear memory. Depletion of A42, in turn, impairs LTP and both spatial and contextual memory. These effects are linked to an increase of the transmitter released during LTP induction and modification of the mechanisms regulating memory acquisition. Both effects require the presence of ␣7-containing nicotinic acetylcholine receptors. We propose a model for the action of A with positive and negative effects on synaptic plasticity and memory representing a continuum, with low concentrations playing a positive and critical role resulting in normal plasticity and memory, and high concentrations playing a negative role resulting in a reduction of plasticity and memory. doi:10.1016/j.neures.2009.09.1484
SY1-A2-4 Regulation of Alzheimer pathology by the calpaincalpastatin system Takaomi Saido RIKEN Brain Science Institute, Japan The mechanism, by which amyloid- peptide (A) accumulation causes neurodegeneration in Alzheimer disease (AD), remains unresolved. Given that A perturbs calcium homeostasis in neurons, we investigated possible involvement of calpain, a calcium-activated protease. We first observed close postsynaptic association of calpain activation with A plaque formation in brains from both AD patients and
Tg mice overexpressing amyloid precursor protein (APP). The mice also exhibited axonal termini dynamically misdirected to calpain activation-positive A plaques. Consistently, cerebrospinal fluids from Tg mice and AD patients contained greater quantity of calpain-cleaved spectrin than controls. Genetic deficiency of calpastatin (CS), calpain-specific inhibitor protein, augmented A amyloidosis, tau phosphorylation, microgliosis, somato-dendritic dystrophy and mortality in APP-Tg mice. In contrast, brain-specific CS overexpression resulted in opposite phenotypes. These observations suggest that calpain activation may underlie A-triggered pathological cascade and thus shall become a relevant pharmacological target in the treatment of AD. doi:10.1016/j.neures.2009.09.1485
SY1-A2-5 Mechanism of neurodegeneration in AD: From the aspect of tau study Akihiko Takashima RIKEN, BSI, Japan Intraneuronal fibrillar depositions of hyperphosphorylated tau protein form neurofibrilary tangles (NFTs), a hallmark of Alzheimer disease (AD). Increasing deposition of tau is found in the brain during aging and in some neurological disorders. Neuronal death is observed in the same brain regions as NFTs, and both neuronal death and NFTs correlate with the duration and severity of illness in AD, although the amount of neuronal death is many times more than the number of NFTs. The elucidation of mutated tau in FTDP-17 conclusively demonstrated that tau dysfunction or abnormality alone could induce neurodegeneration characterized by NFTs, neuronal death, and synapse loss, leading to clinical dementia similar to that found in AD. These pathological change stem from the tau aggregation process, which consists of three distinct tau aggregations, such as hyperphosphorylated tau, granular tau, and fibrillar tau. We clarified the relationship between tau and these pathological changes that hyperphosphorylated tau is involved in synapse loss, granular tau induced neuronal death, and fibrillar tau forms NFT. doi:10.1016/j.neures.2009.09.1486
SY1-A2-6 A immunotherapy: Translation of preclinical biomarkers into the clinic Ronald DeMattos Eli Lilly and Company, Japan Several active and passive immunization approaches for the treatment Alzheimer’s disease (AD) are currently being tested in the clinic. We have shown that the monoclonal antibody m266 binds soluble A selectively and hence cannot operate via mechanisms that depend upon antibody recognition of deposited A(opsonization). An extensive pre-clinical data package has been assembled for m266 that demonstrates its ability to perturb the CNS/plasma A equilibrium, alter soluble CSF A pools, decrease plaque deposition in PDAPP mice and reverse behavioral impairments in PDAPP mice, while at the same time not exacerbating CAA-related microhemorrhage. Our current studies are focused on the translation of the preclinical biomarkers into the clinic. Biomarker results from our recent phase II clinical trial with the humanized antibody solanezumab will be discussed. Particular attention will be focused on the development and implementation of tailored biomarkers for this compound. We believe that this systematic approach to biomarkers can yield important insights on compound mechanisms of action which may facilitate future clinical design. doi:10.1016/j.neures.2009.09.1487
SY1-B1-1 A history of the discovery of adult neurogenesis Tatsunori Seki Tohoku University Graduate School of Medicine, Japan For more than 100 years, there was a dogma that no new neurons are born in the adult brain. The discovery that neurogenesis occurs in the adult mammalian brains is a paradigm shift in the field of neuroscience. Although adult neurogensis was initially discovered in the early 1960s by Joseph Altman, the concept had not been generally accepted until the late 1990s. One of the reasons why this breakthrough was ignored is the used technique to detect new neurons, 3 H-thymidine autoradiography that consumes much time to obtain final results, for example, several weeks. Only a few neuroscientists who did not mind doing the troublesome procedures followed Altman’s studies, and contributed to this field. During the decade of 1990s, there was remarkable technical progress that allowed us to detect easily dividing progenitors in the adult brain, and to examine the exact fate, detailed morphology and various property of developing neural progenitors and immature neurons. On the basis of
Abstracts
SY1-A2-1 Alzheimer disease: From basic study to disease-modifying therapy Takeshi Iwatsubo Dept. Neuropathology, Univ. of Tokyo, Tokyo, Japan ␥-Secretase is a unique aspartic protease involved in intramembrane proteolysis of a set of membrane proteins including APP and Notch. The complex intramembrane structure of ␥-secretase hampered analysis of the mechanisms whereby hydrolysis of transmembrane (TM) substrates is executed within the lipid bilayer. We applied the substituted cysteine accessibility method to examine the structure of PS1 and showed that multiple TM domains (TMD) of PS1 contribute to the formation of a hydrophilic pore within the membrane. Some residues in TMD6, 7, PAL motif, TMD9 and TMD1 are predicted to form a subsite as judged by the pattern of competition of labeling by ␥-secretase inhibitors. Combination of molecular biological and chemical biological approaches will facilitate the understanding of the mechanism of intramembrane cleavage and the development of compounds that selectively inhibit A production. For the clinical development of disease-modifying drugs for Alzheimer disease, establishment of surrogate markers that represent AD pathology is mandatory. Current status of the clinical studies, i.e., ADNI/J-ADNI, will also be discussed. doi:10.1016/j.neures.2009.09.1482
SY1-A2-2 A plaque formation and associated neuritic pathology: Sequence of pathogenic events. Melanie Meyer-Luehmann Adolf-Butenandt Institute, Ludwig-Maximilians-University Munich, Germany Accumulation of amyloid-beta (A) is a neuropathological hallmark of Alzheimer’s disease, which contributes to alterations in neuronal structure and function. However, it is unclear what initiates plaque formation and whether it precedes the changes in neuritic architecture. We performed in vivo multiphoton imaging in APP transgenic mice and found, that plaques form quickly over 24 hours followed by neuritic changes, suggesting that these neuritic changes are a direct consequence of plaque formation. In another experiment, we used a novel in vivo optical reporter and examined the impact of A deposits on neural system function. In APP transgenic mice, neurons and dendritic segments close to plaques (compared to farther away) showed diminished baseline neuronal activity. In contrast to wild type mice, probe response near plaques was not increased by environmental stimuli. These data support the idea that plaques focally impair neural system function. doi:10.1016/j.neures.2009.09.1483
SY1-A2-3 Amyloid-beta: From physiology to pathology Ottavio Arancio Columbia University Medical Center, USA Amyloid- (A) is produced in large amounts in Alzheimer’s disease (AD). We have examined whether and how A interferes with both hippocampal memory and longterm potentiation (LTP), a cellular model of learning and memory. We found that nanomolar levels of A42 impair LTP and both spatial and fear memory through CREB down-regulation. The effects of A, however, are not limited to disruption of synaptic function and memory. In contrast to nanomolar concentrations, low picomolar A42 increases LTP and both spatial and contextual fear memory. Depletion of A42, in turn, impairs LTP and both spatial and contextual memory. These effects are linked to an increase of the transmitter released during LTP induction and modification of the mechanisms regulating memory acquisition. Both effects require the presence of ␣7-containing nicotinic acetylcholine receptors. We propose a model for the action of A with positive and negative effects on synaptic plasticity and memory representing a continuum, with low concentrations playing a positive and critical role resulting in normal plasticity and memory, and high concentrations playing a negative role resulting in a reduction of plasticity and memory. doi:10.1016/j.neures.2009.09.1484
SY1-A2-4 Regulation of Alzheimer pathology by the calpaincalpastatin system Takaomi Saido RIKEN Brain Science Institute, Japan The mechanism, by which amyloid- peptide (A) accumulation causes neurodegeneration in Alzheimer disease (AD), remains unresolved. Given that A perturbs calcium homeostasis in neurons, we investigated possible involvement of calpain, a calcium-activated protease. We first observed close postsynaptic association of calpain activation with A plaque formation in brains from both AD patients and
Tg mice overexpressing amyloid precursor protein (APP). The mice also exhibited axonal termini dynamically misdirected to calpain activation-positive A plaques. Consistently, cerebrospinal fluids from Tg mice and AD patients contained greater quantity of calpain-cleaved spectrin than controls. Genetic deficiency of calpastatin (CS), calpain-specific inhibitor protein, augmented A amyloidosis, tau phosphorylation, microgliosis, somato-dendritic dystrophy and mortality in APP-Tg mice. In contrast, brain-specific CS overexpression resulted in opposite phenotypes. These observations suggest that calpain activation may underlie A-triggered pathological cascade and thus shall become a relevant pharmacological target in the treatment of AD. doi:10.1016/j.neures.2009.09.1485
SY1-A2-5 Mechanism of neurodegeneration in AD: From the aspect of tau study Akihiko Takashima RIKEN, BSI, Japan Intraneuronal fibrillar depositions of hyperphosphorylated tau protein form neurofibrilary tangles (NFTs), a hallmark of Alzheimer disease (AD). Increasing deposition of tau is found in the brain during aging and in some neurological disorders. Neuronal death is observed in the same brain regions as NFTs, and both neuronal death and NFTs correlate with the duration and severity of illness in AD, although the amount of neuronal death is many times more than the number of NFTs. The elucidation of mutated tau in FTDP-17 conclusively demonstrated that tau dysfunction or abnormality alone could induce neurodegeneration characterized by NFTs, neuronal death, and synapse loss, leading to clinical dementia similar to that found in AD. These pathological change stem from the tau aggregation process, which consists of three distinct tau aggregations, such as hyperphosphorylated tau, granular tau, and fibrillar tau. We clarified the relationship between tau and these pathological changes that hyperphosphorylated tau is involved in synapse loss, granular tau induced neuronal death, and fibrillar tau forms NFT. doi:10.1016/j.neures.2009.09.1486
SY1-A2-6 A immunotherapy: Translation of preclinical biomarkers into the clinic Ronald DeMattos Eli Lilly and Company, Japan Several active and passive immunization approaches for the treatment Alzheimer’s disease (AD) are currently being tested in the clinic. We have shown that the monoclonal antibody m266 binds soluble A selectively and hence cannot operate via mechanisms that depend upon antibody recognition of deposited A(opsonization). An extensive pre-clinical data package has been assembled for m266 that demonstrates its ability to perturb the CNS/plasma A equilibrium, alter soluble CSF A pools, decrease plaque deposition in PDAPP mice and reverse behavioral impairments in PDAPP mice, while at the same time not exacerbating CAA-related microhemorrhage. Our current studies are focused on the translation of the preclinical biomarkers into the clinic. Biomarker results from our recent phase II clinical trial with the humanized antibody solanezumab will be discussed. Particular attention will be focused on the development and implementation of tailored biomarkers for this compound. We believe that this systematic approach to biomarkers can yield important insights on compound mechanisms of action which may facilitate future clinical design. doi:10.1016/j.neures.2009.09.1487
SY1-B1-1 A history of the discovery of adult neurogenesis Tatsunori Seki Tohoku University Graduate School of Medicine, Japan For more than 100 years, there was a dogma that no new neurons are born in the adult brain. The discovery that neurogenesis occurs in the adult mammalian brains is a paradigm shift in the field of neuroscience. Although adult neurogensis was initially discovered in the early 1960s by Joseph Altman, the concept had not been generally accepted until the late 1990s. One of the reasons why this breakthrough was ignored is the used technique to detect new neurons, 3 H-thymidine autoradiography that consumes much time to obtain final results, for example, several weeks. Only a few neuroscientists who did not mind doing the troublesome procedures followed Altman’s studies, and contributed to this field. During the decade of 1990s, there was remarkable technical progress that allowed us to detect easily dividing progenitors in the adult brain, and to examine the exact fate, detailed morphology and various property of developing neural progenitors and immature neurons. On the basis of