- Email: [email protected]
TRANSMISSION AND SPREADING OF TAUOPATHIES IN TRANSGENIC MOUSE BRAIN
P162
F2-04-03
Plenary Sessions: PL-02
Florence Clavaguera1, Bernardino Ghetti2, Gabriel Schweighauser3, Hiroyasu Akatsu4, J€ urgen Hench3, Markus Tolnay3, Michel Goedert5, 1 Institute of Pathology, University Hospital, Basel, Switzerland; 2Indiana Alzheimer Disease Center and Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, United States; 3 Institute of Pathology, University Hospital, Basel, Switzerland; 4Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan; 5Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer’s disease (AD), tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). In AD and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. Methods: We have demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. More recently, we have shown that the intracerebral injection of brain extracts from humans who had died with various tauopathies into ALZ17 mice formed argyrophilic tau inclusions. Results: Following the injection of the corresponding brain extracts we recapitulated the hallmark lesions of AGD, PSPand CBD. Conclusions: These findings point the existence of different tau strains and suggest that once tau aggregates have formed in discrete brain areas they become self-propagating and spread in a prion-like manner.Similar to prion diseases, which can be transmitted via multiple routes (including the intraperitoneal route), we demonstrated that the intraperitoneal injection of tau seeds can also induce intracerebral tauopathy. F2-04-04
MONDAY, JULY 14, 2014 PLENARY SESSIONS PL-02
TRANSMISSION AND SPREADING OF TAUOPATHIES IN TRANSGENIC MOUSE BRAIN
FIRST-IN-MAN AND FIRST-IN-CLASS TAU VACCINE
Michal Novak, Axon Neuroscience SE, Bratislava, Slovakia. Contact e-mail: [email protected] Background: Misfolded Alzheimer tau is a key feature of Alzheimer’s disease and related tauopathies. Alzheimer tau correlates with clinical symptomatology and disease progression. Methods: Tau peptide was designed to develop active vaccine - AADvac1 targeting structural determinants on tau that are essential for pathological tau-tau interaction. Efficacy of active vaccine was tested on transgenic rats and mice expressing human misfolded truncated tau. Toxicology and safety pharmacology studies were done on mice, rats, rabbits and dogs. Results: We found that Alzheimer tau displays infectious properties and can spread throughout the brain. We identified the most vulnerable area of Alzheimer tau - the Achilles heel, that is responsible for tau-tau interactions. Using knowledge of its 3D structure, we produced tau peptide vaccine conjugated to the immunogenic carrier protein keyhole limpet hemocyanin (KLH). We confirmed its in vivo efficacy in preclinical studies on AD transgenic rat and mouse models. Preclinical toxicology and safety pharmacology studies on AADvac1 vaccine allowed the establishing of a no adverse effect level at the dosing planned for human clinical studies. Vaccine was shown to be immunogenic in mice, rats and rabbits, inducing high affinity anti-tau antibodies for pathological tau. Moreover, the immune response to the active vaccine was shifted toward T-cell independent Th2 humoral pathway underlying its safety. The first phase of human clinical trials started in July 2013, featuring a three month double blind design followed by a three month open labelled study with administration of up to six doses of AADvac1. As of today patients have received up to six doses of AADvac1 with no adverse effects. Conclusions: Our results suggest that active immunisation against misfolded Alzheimer tau constitutes a safe and well targeted treatment for disease modifying therapy for Alzheimer’s disease.
PL-02-01
NUTRITION AND PREVENTION
Francine Grodstein, Brigham and Women’s Hospital, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: There is abundant evidence of benefits of diet in reducing chronic diseases and health conditions. Prominent examples include the DASH trials (n¼459), in which adherence to a diet rich in fruits, vegetables, chicken, fish, nuts, and whole grains reduced blood pressure. The Diabetes Prevention Program (n¼3234) demonstrated that healthy diet and exercise reduced diabetes development by 58% over 3 years compared to placebo. The recent PREDIMED trial, with over 7000 participants, tested a Mediterranean diet for 5 years, establishing a 30% decrease in cardiovascular disease and a similar 30% reduction in type 2 diabetes compared to placebo. Methods: These successful diet studies have several factors in common. All tested diet patterns rather than specific nutrients; all those of clinical endpoints included thousands of participants, followed for several years or more; and all were preceded by large-scale, observational epidemiologic studies which provided fairly consistent evidence of health benefits. Results: In contrast, in dementia, diet research is dominated by studies of single nutrients and trials of modest size and moderate duration. For example, in a recent review of observational studies of Mediterranean diet and MCI/dementia, <7 cohort studies were identified which provided relevant data. Moreover, in a review of ongoing randomized trials which include a diet pattern component, all had <2000 participants and treatments of 2–4 years at most. Conclusions: While it will be many years before large, long-term diet trials can be developed and then completed, in the meantime larger observational studies could meaningfully advance the field. A relatively simple and immediate solution could involve creation of a consortium to pool data from multiple cohorts on diet and dementia; this would yield results with higher precision and further detail than are currently available. Such information on exact food type and quantity (eg, eat dark, fatty fish for at least two meals per week) would be critical both for developing actionable public health guidelines and for planning future studies. This approach has already proven successful in discovering Alzheimer genes, and that model could be transferred to nongenetic research – as has already been done for dietary studies of other chronic diseases, leading to their prevention recommendations. PL-02-02
PREDICTING CLINICAL PROGRESSION IN SUBJECTIVE COGNITIVE DECLINE
Wiesje M. van der Flier, VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: By now, we know that the earliest brain changes leading to AD occur 15 to 20 years before onset of the disease. Subjective cognitive decline may herald the first symptoms of AD. As such, patients presenting with subjective cognitive decline at a memory clinic, potentially form an enriched population to study preclinical AD. The Subjective Cognitive Decline Initiative (SCD-I) working group has developed a conceptual framework and consensus terminology, to allow the systematic study of this important group of patients. Research criteria are presented and a list of features increasing the likelihood of the presence of preclinical AD is proposed. Methods: In the Amsterdam Dementia Cohort, we followed a large group of patients with Subjective Cognitive Decline over time, and found that the preclinical dementia stages as developed under auspices of NIA-AA strongly predict clinical progression, defined as progression to MCI or dementia due to AD. Moreover, predictive value was modified by APOE genotype, with predictive value of preclinical AD stages particularly strong in APOE e4 noncarriers. Results: We also found that in patients with normal biomarkers memory function tended to improve over time. As a next step, we evaluated a panel of protein biomarkers, i.e. concentration of ApoE, ApoJ, and ApoA in blood and CSF to elucidate the pathways along which the disease may develop.Based on MRI, patients with subjective cognitive decline have been shown to have more atrophy and less functional connectivity, than healthy elderly. We evaluated the predictive value of grey matter connectivity for
F2-04-03
Plenary Sessions: PL-02
Florence Clavaguera1, Bernardino Ghetti2, Gabriel Schweighauser3, Hiroyasu Akatsu4, J€ urgen Hench3, Markus Tolnay3, Michel Goedert5, 1 Institute of Pathology, University Hospital, Basel, Switzerland; 2Indiana Alzheimer Disease Center and Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, United States; 3 Institute of Pathology, University Hospital, Basel, Switzerland; 4Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan; 5Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom. Contact e-mail: [email protected] Background: Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer’s disease (AD), tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). In AD and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. Methods: We have demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. More recently, we have shown that the intracerebral injection of brain extracts from humans who had died with various tauopathies into ALZ17 mice formed argyrophilic tau inclusions. Results: Following the injection of the corresponding brain extracts we recapitulated the hallmark lesions of AGD, PSPand CBD. Conclusions: These findings point the existence of different tau strains and suggest that once tau aggregates have formed in discrete brain areas they become self-propagating and spread in a prion-like manner.Similar to prion diseases, which can be transmitted via multiple routes (including the intraperitoneal route), we demonstrated that the intraperitoneal injection of tau seeds can also induce intracerebral tauopathy. F2-04-04
MONDAY, JULY 14, 2014 PLENARY SESSIONS PL-02
TRANSMISSION AND SPREADING OF TAUOPATHIES IN TRANSGENIC MOUSE BRAIN
FIRST-IN-MAN AND FIRST-IN-CLASS TAU VACCINE
Michal Novak, Axon Neuroscience SE, Bratislava, Slovakia. Contact e-mail: [email protected] Background: Misfolded Alzheimer tau is a key feature of Alzheimer’s disease and related tauopathies. Alzheimer tau correlates with clinical symptomatology and disease progression. Methods: Tau peptide was designed to develop active vaccine - AADvac1 targeting structural determinants on tau that are essential for pathological tau-tau interaction. Efficacy of active vaccine was tested on transgenic rats and mice expressing human misfolded truncated tau. Toxicology and safety pharmacology studies were done on mice, rats, rabbits and dogs. Results: We found that Alzheimer tau displays infectious properties and can spread throughout the brain. We identified the most vulnerable area of Alzheimer tau - the Achilles heel, that is responsible for tau-tau interactions. Using knowledge of its 3D structure, we produced tau peptide vaccine conjugated to the immunogenic carrier protein keyhole limpet hemocyanin (KLH). We confirmed its in vivo efficacy in preclinical studies on AD transgenic rat and mouse models. Preclinical toxicology and safety pharmacology studies on AADvac1 vaccine allowed the establishing of a no adverse effect level at the dosing planned for human clinical studies. Vaccine was shown to be immunogenic in mice, rats and rabbits, inducing high affinity anti-tau antibodies for pathological tau. Moreover, the immune response to the active vaccine was shifted toward T-cell independent Th2 humoral pathway underlying its safety. The first phase of human clinical trials started in July 2013, featuring a three month double blind design followed by a three month open labelled study with administration of up to six doses of AADvac1. As of today patients have received up to six doses of AADvac1 with no adverse effects. Conclusions: Our results suggest that active immunisation against misfolded Alzheimer tau constitutes a safe and well targeted treatment for disease modifying therapy for Alzheimer’s disease.
PL-02-01
NUTRITION AND PREVENTION
Francine Grodstein, Brigham and Women’s Hospital, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: There is abundant evidence of benefits of diet in reducing chronic diseases and health conditions. Prominent examples include the DASH trials (n¼459), in which adherence to a diet rich in fruits, vegetables, chicken, fish, nuts, and whole grains reduced blood pressure. The Diabetes Prevention Program (n¼3234) demonstrated that healthy diet and exercise reduced diabetes development by 58% over 3 years compared to placebo. The recent PREDIMED trial, with over 7000 participants, tested a Mediterranean diet for 5 years, establishing a 30% decrease in cardiovascular disease and a similar 30% reduction in type 2 diabetes compared to placebo. Methods: These successful diet studies have several factors in common. All tested diet patterns rather than specific nutrients; all those of clinical endpoints included thousands of participants, followed for several years or more; and all were preceded by large-scale, observational epidemiologic studies which provided fairly consistent evidence of health benefits. Results: In contrast, in dementia, diet research is dominated by studies of single nutrients and trials of modest size and moderate duration. For example, in a recent review of observational studies of Mediterranean diet and MCI/dementia, <7 cohort studies were identified which provided relevant data. Moreover, in a review of ongoing randomized trials which include a diet pattern component, all had <2000 participants and treatments of 2–4 years at most. Conclusions: While it will be many years before large, long-term diet trials can be developed and then completed, in the meantime larger observational studies could meaningfully advance the field. A relatively simple and immediate solution could involve creation of a consortium to pool data from multiple cohorts on diet and dementia; this would yield results with higher precision and further detail than are currently available. Such information on exact food type and quantity (eg, eat dark, fatty fish for at least two meals per week) would be critical both for developing actionable public health guidelines and for planning future studies. This approach has already proven successful in discovering Alzheimer genes, and that model could be transferred to nongenetic research – as has already been done for dietary studies of other chronic diseases, leading to their prevention recommendations. PL-02-02
PREDICTING CLINICAL PROGRESSION IN SUBJECTIVE COGNITIVE DECLINE
Wiesje M. van der Flier, VU University Medical Center, Amsterdam, Netherlands. Contact e-mail: [email protected] Background: By now, we know that the earliest brain changes leading to AD occur 15 to 20 years before onset of the disease. Subjective cognitive decline may herald the first symptoms of AD. As such, patients presenting with subjective cognitive decline at a memory clinic, potentially form an enriched population to study preclinical AD. The Subjective Cognitive Decline Initiative (SCD-I) working group has developed a conceptual framework and consensus terminology, to allow the systematic study of this important group of patients. Research criteria are presented and a list of features increasing the likelihood of the presence of preclinical AD is proposed. Methods: In the Amsterdam Dementia Cohort, we followed a large group of patients with Subjective Cognitive Decline over time, and found that the preclinical dementia stages as developed under auspices of NIA-AA strongly predict clinical progression, defined as progression to MCI or dementia due to AD. Moreover, predictive value was modified by APOE genotype, with predictive value of preclinical AD stages particularly strong in APOE e4 noncarriers. Results: We also found that in patients with normal biomarkers memory function tended to improve over time. As a next step, we evaluated a panel of protein biomarkers, i.e. concentration of ApoE, ApoJ, and ApoA in blood and CSF to elucidate the pathways along which the disease may develop.Based on MRI, patients with subjective cognitive decline have been shown to have more atrophy and less functional connectivity, than healthy elderly. We evaluated the predictive value of grey matter connectivity for