- Email: [email protected]
85 Alzheimer therapy: present and future
S36
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
human brain. Using non-denaturing size exclusion chromatography (SEC) we identified A species which eluted in four different fractions, at least one of which was recognised by an aggregate-specific antibody. These data indicate that patient-derived A which migrate on SDS-PAGE as monomer and dimer emanate in part from larger assemblies. Moreover, the synaptotoxic activity of brain-extracted A was neutralized by antibodies raised to assemblies of covalently stabilized A dimers. A-containing complexes which eluted from SEC with masses of ⬃56-114 kDa, but migrated on SDS-PAGE as a dimer, had predicted primary sequences identical to those detected in fractions that eluted as authentic dimers. Whereas, A-containing complexes that eluted from SEC in higher molecular weight fractions were predicted to be enriched in N-terminally truncated A allotypes. These data suggest that therapeutic targeting of A dimers (or assemblies thereof) may overcome the synaptic failure that characterizes AD.
83
LADOSTIGIL, A NOVEL MULTIFUNCTIONAL DRUG FOR THE PREVENTION AND TREATMENT OF ALZHEIMER’S DISEASE
Marta Weinstock-Rosin, Department of Pharmacology, Institute of Drug Research, Jerusalem, Israel. Contact e-mail: [email protected] Ladostigil was designed as an inhibitor of acetylcholinesterase (AChE) and butylcholinesterase and a brain selective, irreversible inhibitor of monoamine oxidase (MAO)-A and B. AChE inhibitory activity results from metabolites, RMCPAI and R-CAI formed in the liver and the brainselective MAO inhibition, from the formation of R-HPAI through hydrolysis of the carbamate by cholinesterase. The drug is currently being tested in a phase IIb trial in Europe in patients with Alzheimer’s disease (AD) and depression. Effective therapies should be commenced at the prodromal stage of AD when there is only mild cognitive impairment (MCI). The brains of such subjects show evidence of oxidative stress and glial activation even in the absence of beta amyloid plaques. Ladostigil and its metabolites protect against cytotoxicity induced by oxidative and nitrative stress in cell cultures by preventing the opening of the mitochondrial transition pore and apoptosis. They also reduce the release of nitric oxide, TNF-␣ and IL-1 from activated microglia. Daily administration of ladostigil (1 mg/kg/day) for 6 months to 16 month old rats prevented the loss of object recognition and spatial memory. This was associated with a reduction in glial activation in the hippocampus, fornix and parietal cortex and reduction to the levels found in young rats of age-induced increases in mRNAs of inducible nitric oxide synthase (iNOS) in the hippocampus and cytokines, IL-1, TNF-␣ and IL-6 in the
parietal cortex. A higher dose of ladostigil (8.5 mg/kg) that inhibited brain AChE by 30-40% was necessary to reverse the object recognition memory deficits in aged rats. The ability of ladostigil to reduce oxidative stress, apoptosis and the release of pro-inflammatory cytokines may enable it to slow the progression of MCI to AD. The drug is currently in a trial in MCI patients in Israel and Austria and Germany for this purpose.
84
GLOBAL PHARMACOECONOMICS OF ALZHEIMER’S DISEASE IN LIGHT OF POTENTIAL COST EFFECTIVENESS OF DISEASE MODIFYING TREATMENT
Anders Wimo, Alzheimer’s Disease Research Center, NCS, Karolinska Institutet, Stockholm, Sweden. Contact e-mail: [email protected] Today, about 36 million people suffer from Alzheimer’s Disease (AD) and other dementias worldwide. The global societal costs of dementia have been estimated to be 604 billion US$. This enormous psycho social and economic burden highlights the need for cost effective treatments. Current pharmacological treatments of AD have significant but clinically rather modest effects and therefore there is hope that disease modifying drugs (DMD) will be on the market. However, to analyse the cost-effectiveness of DMDs is challenging and empirical studies need to be combined with economic modelling. Duration of treatment, price of drugs and effects on survival are crucial when the long term cost effectiveness is analysed and estimated. Another challenging scenario is the fact that a majority of people with dementia worldwide live in low and middle income countries (LMIC). So far, the availability of current drugs in these countries is limited. The great economic growth in LMIC with increasing demands for treatment offer great challenges for pharmaceutical companies but also in the adaption of cost effectiveness methodology. For example, the impact of informal care is more of interest than postponing nursing home care.
85
ALZHEIMER THERAPY: PRESENT AND FUTURE
Bengt Winblad, Karolinska Institutet Alzheimer Disease Research Center, Huddinge, Sweden. Contact e-mail: [email protected] Alzheimer disease (AD) is the most common cause of dementia in advanced age. Currently available medications improve AD symptoms and development of disease-modifying drugs is a very active area of research, which includes cholinergic, anti-amyloid compounds, drugs targeting tau-
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
protein or mitochondria, neurotrophins and other therapeutic approaches. The amyloid cascade hypothesis dominates current drug development strategies, but the exact role of A in the AD pathogenesis is not yet clear, and so is the therapeutic role of A removal. Identification of effective disease-modifying drugs will benefit from understanding the interplay between mechanisms causing neurodegeneration in AD. Combined therapy could be a more effective strategy to halt AD progression. Solving methodological problems in clinical trials on AD - including use of standardized diagnostic criteria able to identify homogeneous group of patients, appropriate treatment duration and measures of disease-modifying effects - will help finding a cure for AD. The lecture will summarize current treatment possibilities for AD and give an overview of the main findings of new therapeutics in AD, focusing mainly on compounds in the human testing phase.
86
ANIMAL MODELS FOR PRECLINICAL TESTING OF EARLY AD?
Manfred Windisch, JSW LifeSciences GmbH, Graz, Austria. Contact e-mail: [email protected] Well established animal models are a requirement for a successful proof of concept in each drug development program, and the main question is how to achieve a high predictive value. The fact that no really useful naturally occurring disease models are existing for Alzheimer’s disease advocates for the use of transgenic mouse models, either resembling particular features of the AD brain pathology, or even a status close to the human disease. So far only complex and multiple transgenic mouse or rat models are really developing all the pathological hallmarks accompanied by functional (cognitive) deficits. The big problem is that most of these models are artificial and conclusions about the human disease should be drawn only with extreme caution. But independent which model is suggested they all have the advantage that the time of onset and the course of the development of the brain pathology is well characterised. Therefore we practically know that all of these animals are suffering already from “prodromal AD” before we can detect real changes. This allows now to determine an early presymptomatic start of the treatment and the further development of the disease can be directly compared to untreated control groups. This possibility allows to draw conclusions about disease modification, delay of progression or even prevention of disease onset (maybe too optimistic!). Such investigations may help us in the future to learn about the most ideal time to start treatment
S37
in humans, and these usually highly progressive animal models will also give us at least some estimates what can be achieved in terms of disease modification. The predictive value of such results must again carefully be discussed.
87
NOVEL NEW MULTI TARGET ANTI ALZHEIMER DRUGS WITH NEUROPROTECTIVE AND NEURORESTORATIVE ACTIVITIES
Moussa B. H. Youdim, Technion-Israel Institute of Technology, Haifa, Israel. Contact e-mail: [email protected] The role of iron and oxidative stress in Alzheimer’s Disease (AD) lead us to develop non-toxic, lipophilic propargylamine, brain permeable multifunctional compounds with iron chelation, cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory moieties properties for AD. We investigated the neuroprotective and neurorestorative effects of M30, HLA20 and M30P in transgenic APP/PS1 (Tg) mice model of AD. These studies include regulation of A aggregation and plaque areas, holo-APP expression levels and APP-processing mechanisms and cognitive abilities, since the 5’ untranslated region of APP mRNA has a functional iron-responsive element. Comprehensive behavioral batteries determined at 10 month of age revealed that transgenic APPswe/PS1 mice given M30 during that period were protected from cognitive impairments in a verity of tasks of spatial learning and memory retention, working memory, learning abilities, anxiety level, and memory for the novel food and nesting behavior. Non treated transgenic mice remained impaired in all of these cognitive tasks/ domains. M30 markedly reduced the levels of holo- APP and -CTF in the frontal cortex, hippocampus and parietal cortex of APP/PS1 treated mice compared to non-treated animals. Coordinately, the levels of cerebral amyloidogenic A peptide in soluble and insoluble fractions and the number of A plaques and dimeric A contents in the frontal cortex, hippocampus and parietal cortex were decreased in M30-Tg mice as compared to non-treated animals. Regarding aspects of cell signaling pathways associated with Alzheimer’s disease (AD) pathology, M30 activated HIF, induce cell cycle arrest at G0/G1, enhanced the levels of BDNF, GDNF VEGF, phospho-AKT and phospho- glycogen synthase kinase (GSK)-3 and attenuated Tau phosphorylation. Being potent MAO A and B inhbitor it has anti Parkinson ans anti depressant activies. Our findings provide support for long-term M30 therapy as primary strategy for treatment of AD and Lowy Body disease aspossible disease modifying agent.
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
human brain. Using non-denaturing size exclusion chromatography (SEC) we identified A species which eluted in four different fractions, at least one of which was recognised by an aggregate-specific antibody. These data indicate that patient-derived A which migrate on SDS-PAGE as monomer and dimer emanate in part from larger assemblies. Moreover, the synaptotoxic activity of brain-extracted A was neutralized by antibodies raised to assemblies of covalently stabilized A dimers. A-containing complexes which eluted from SEC with masses of ⬃56-114 kDa, but migrated on SDS-PAGE as a dimer, had predicted primary sequences identical to those detected in fractions that eluted as authentic dimers. Whereas, A-containing complexes that eluted from SEC in higher molecular weight fractions were predicted to be enriched in N-terminally truncated A allotypes. These data suggest that therapeutic targeting of A dimers (or assemblies thereof) may overcome the synaptic failure that characterizes AD.
83
LADOSTIGIL, A NOVEL MULTIFUNCTIONAL DRUG FOR THE PREVENTION AND TREATMENT OF ALZHEIMER’S DISEASE
Marta Weinstock-Rosin, Department of Pharmacology, Institute of Drug Research, Jerusalem, Israel. Contact e-mail: [email protected] Ladostigil was designed as an inhibitor of acetylcholinesterase (AChE) and butylcholinesterase and a brain selective, irreversible inhibitor of monoamine oxidase (MAO)-A and B. AChE inhibitory activity results from metabolites, RMCPAI and R-CAI formed in the liver and the brainselective MAO inhibition, from the formation of R-HPAI through hydrolysis of the carbamate by cholinesterase. The drug is currently being tested in a phase IIb trial in Europe in patients with Alzheimer’s disease (AD) and depression. Effective therapies should be commenced at the prodromal stage of AD when there is only mild cognitive impairment (MCI). The brains of such subjects show evidence of oxidative stress and glial activation even in the absence of beta amyloid plaques. Ladostigil and its metabolites protect against cytotoxicity induced by oxidative and nitrative stress in cell cultures by preventing the opening of the mitochondrial transition pore and apoptosis. They also reduce the release of nitric oxide, TNF-␣ and IL-1 from activated microglia. Daily administration of ladostigil (1 mg/kg/day) for 6 months to 16 month old rats prevented the loss of object recognition and spatial memory. This was associated with a reduction in glial activation in the hippocampus, fornix and parietal cortex and reduction to the levels found in young rats of age-induced increases in mRNAs of inducible nitric oxide synthase (iNOS) in the hippocampus and cytokines, IL-1, TNF-␣ and IL-6 in the
parietal cortex. A higher dose of ladostigil (8.5 mg/kg) that inhibited brain AChE by 30-40% was necessary to reverse the object recognition memory deficits in aged rats. The ability of ladostigil to reduce oxidative stress, apoptosis and the release of pro-inflammatory cytokines may enable it to slow the progression of MCI to AD. The drug is currently in a trial in MCI patients in Israel and Austria and Germany for this purpose.
84
GLOBAL PHARMACOECONOMICS OF ALZHEIMER’S DISEASE IN LIGHT OF POTENTIAL COST EFFECTIVENESS OF DISEASE MODIFYING TREATMENT
Anders Wimo, Alzheimer’s Disease Research Center, NCS, Karolinska Institutet, Stockholm, Sweden. Contact e-mail: [email protected] Today, about 36 million people suffer from Alzheimer’s Disease (AD) and other dementias worldwide. The global societal costs of dementia have been estimated to be 604 billion US$. This enormous psycho social and economic burden highlights the need for cost effective treatments. Current pharmacological treatments of AD have significant but clinically rather modest effects and therefore there is hope that disease modifying drugs (DMD) will be on the market. However, to analyse the cost-effectiveness of DMDs is challenging and empirical studies need to be combined with economic modelling. Duration of treatment, price of drugs and effects on survival are crucial when the long term cost effectiveness is analysed and estimated. Another challenging scenario is the fact that a majority of people with dementia worldwide live in low and middle income countries (LMIC). So far, the availability of current drugs in these countries is limited. The great economic growth in LMIC with increasing demands for treatment offer great challenges for pharmaceutical companies but also in the adaption of cost effectiveness methodology. For example, the impact of informal care is more of interest than postponing nursing home care.
85
ALZHEIMER THERAPY: PRESENT AND FUTURE
Bengt Winblad, Karolinska Institutet Alzheimer Disease Research Center, Huddinge, Sweden. Contact e-mail: [email protected] Alzheimer disease (AD) is the most common cause of dementia in advanced age. Currently available medications improve AD symptoms and development of disease-modifying drugs is a very active area of research, which includes cholinergic, anti-amyloid compounds, drugs targeting tau-
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
protein or mitochondria, neurotrophins and other therapeutic approaches. The amyloid cascade hypothesis dominates current drug development strategies, but the exact role of A in the AD pathogenesis is not yet clear, and so is the therapeutic role of A removal. Identification of effective disease-modifying drugs will benefit from understanding the interplay between mechanisms causing neurodegeneration in AD. Combined therapy could be a more effective strategy to halt AD progression. Solving methodological problems in clinical trials on AD - including use of standardized diagnostic criteria able to identify homogeneous group of patients, appropriate treatment duration and measures of disease-modifying effects - will help finding a cure for AD. The lecture will summarize current treatment possibilities for AD and give an overview of the main findings of new therapeutics in AD, focusing mainly on compounds in the human testing phase.
86
ANIMAL MODELS FOR PRECLINICAL TESTING OF EARLY AD?
Manfred Windisch, JSW LifeSciences GmbH, Graz, Austria. Contact e-mail: [email protected] Well established animal models are a requirement for a successful proof of concept in each drug development program, and the main question is how to achieve a high predictive value. The fact that no really useful naturally occurring disease models are existing for Alzheimer’s disease advocates for the use of transgenic mouse models, either resembling particular features of the AD brain pathology, or even a status close to the human disease. So far only complex and multiple transgenic mouse or rat models are really developing all the pathological hallmarks accompanied by functional (cognitive) deficits. The big problem is that most of these models are artificial and conclusions about the human disease should be drawn only with extreme caution. But independent which model is suggested they all have the advantage that the time of onset and the course of the development of the brain pathology is well characterised. Therefore we practically know that all of these animals are suffering already from “prodromal AD” before we can detect real changes. This allows now to determine an early presymptomatic start of the treatment and the further development of the disease can be directly compared to untreated control groups. This possibility allows to draw conclusions about disease modification, delay of progression or even prevention of disease onset (maybe too optimistic!). Such investigations may help us in the future to learn about the most ideal time to start treatment
S37
in humans, and these usually highly progressive animal models will also give us at least some estimates what can be achieved in terms of disease modification. The predictive value of such results must again carefully be discussed.
87
NOVEL NEW MULTI TARGET ANTI ALZHEIMER DRUGS WITH NEUROPROTECTIVE AND NEURORESTORATIVE ACTIVITIES
Moussa B. H. Youdim, Technion-Israel Institute of Technology, Haifa, Israel. Contact e-mail: [email protected] The role of iron and oxidative stress in Alzheimer’s Disease (AD) lead us to develop non-toxic, lipophilic propargylamine, brain permeable multifunctional compounds with iron chelation, cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory moieties properties for AD. We investigated the neuroprotective and neurorestorative effects of M30, HLA20 and M30P in transgenic APP/PS1 (Tg) mice model of AD. These studies include regulation of A aggregation and plaque areas, holo-APP expression levels and APP-processing mechanisms and cognitive abilities, since the 5’ untranslated region of APP mRNA has a functional iron-responsive element. Comprehensive behavioral batteries determined at 10 month of age revealed that transgenic APPswe/PS1 mice given M30 during that period were protected from cognitive impairments in a verity of tasks of spatial learning and memory retention, working memory, learning abilities, anxiety level, and memory for the novel food and nesting behavior. Non treated transgenic mice remained impaired in all of these cognitive tasks/ domains. M30 markedly reduced the levels of holo- APP and -CTF in the frontal cortex, hippocampus and parietal cortex of APP/PS1 treated mice compared to non-treated animals. Coordinately, the levels of cerebral amyloidogenic A peptide in soluble and insoluble fractions and the number of A plaques and dimeric A contents in the frontal cortex, hippocampus and parietal cortex were decreased in M30-Tg mice as compared to non-treated animals. Regarding aspects of cell signaling pathways associated with Alzheimer’s disease (AD) pathology, M30 activated HIF, induce cell cycle arrest at G0/G1, enhanced the levels of BDNF, GDNF VEGF, phospho-AKT and phospho- glycogen synthase kinase (GSK)-3 and attenuated Tau phosphorylation. Being potent MAO A and B inhbitor it has anti Parkinson ans anti depressant activies. Our findings provide support for long-term M30 therapy as primary strategy for treatment of AD and Lowy Body disease aspossible disease modifying agent.