DWIH Tokyo Conference Proceedings

German Research and Innovation Forum Tokyo | Conference Proceedings

German-Japanese Symposium
on Ageing and Neurodegeneration
12 December 2011 | Osaka, Japan

Table of Contents
02

Greetings

03

Challenges and Opportunities in
Neuro­d egenerative Disease Research

11

Presentations

22

Panel Discussion and Comments from the Audience

24

Editorial Notes
References
List of Contributors

GREETINGS

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Ageing and neurodegeneration are challenges for both research and society. Due todemographic developments, the proportion of elderly people in the population is growing in Japan as well as in Germany. As a result, an increasing number of people is affectedby neurodegenerative diseases.
What are the challenges currently facing researchers in Japan and Germany? What are
the social, ethical, and economic implications of this trend, and what can societies do in
response? The German-Japanese symposium co-organized by the German Research andInnovation Forum Tokyo (Deutsches Wissenschafts- und Innovationshaus Tokyo – DWIHTokyo) and the German Center for Neurodegenerative Diseases (Deutsches Zentrum fürNeurodegenerative Erkrankungen e.V. – DZNE) in Osaka in December 2011, provided aplatform for high-level exchange on these compelling issues.
Around 100 experts from research and industry debated in Osaka why ageing is a main
risk factor for neurodegenerative diseases such as Alzheimer’s or Parkinson’s, how new
therapies and more effective preventative measures can be designed and how German
and Japanese researchers can jointly push forward in these fields.
We are pleased to present to you a summary of the symposium’s proceedings, which willcontribute to making its outcomes known to the wider scientific community.
Professor Dr. Dr. Pierluigi Nicotera

Marijke Wahlers

Scientific Director and Chairman of the

Head of International Department,

Executive Board

German Rectors’ Conference

German Center for Neurodegenerative

German Research and Innovation

DiseasesForum Tokyo

Challenges and Opportunities in Neurodegenerative Disease Research
Sarah A. Jewell, Pierluigi Nicotera

Perhaps no biomedical field better exemplifies the urgency, excitement and challenge oftranslational research than the field of neurodegenerative diseases. Despite important
breakthroughs in our understanding of the pathogenetic mechanisms underlying these
conditions, and major investments in clinical trials of promising pharmaceuticals, ourprevious attempts to bring disease-modifying treatments “from the bench to the bedside” have been disappointing. This brief review outlines areas of recent progress and current knowledge gaps in the two most prevalent neurodegenerative disorders, Alzheimer’sand Parkinson’s diseases (AD & PD), complementing the individual presentations given
at the German-Japanese Symposium on Ageing and Neurodegeneration.

General Considerations

There is no doubt that effective interventions against neurodegenerative disorders are urgently needed. The personal suffering associated with the progressive loss of cognitive,
emotional and/or motor function is enormous. The societal burden is also substantial,
and projections of future disease prevalence and costs in an increasingly aged population
are truly staggering. A recent European Brain Council study of the size and burden ofbrain disorders in Europe estimated that 6.34 million people have been diagnosed withdementia (including AD) and 1.2 million have PD; the total costs for these two disorders
in 2010 were calculated to be 105 billion € and 14 billion €, respectively [1]. The number ofindividuals with PD in the world’s most populous nations will double by 2030 [2], and the
Alzheimer’s Association reports an expected five-fold increase in care costs for AD in the
USA from USD 172 billion to USD 1 trillion by 2050. Although our goal is ultimately
to prevent or cure these diseases completely, even partially effective interventions would
render substantial benefits. For example, it has been estimated that the introduction of ameans to simply delay AD onset by five years would reduce care costs by 40% [3].
It is also clear that advances in the laboratory have led to dramatic recent progress in our
understanding of how neurodegenerative diseases develop. We now know much more
about how genetic factors influence disease risk, thanks to genome-wide association
studies in humans and new transgenic laboratory animal models. Genetic mutations are
the predominant cause of neurodegenerative disease in only a small subset of cases (e.g.
certain mutations in presenilin or amyloid precursor protein are sufficient to cause early
onset AD). Far more disease is caused by complex interactions between genetic constitution and non-genetic factors (including co-existing health conditions, nutritional status
and environmental exposures such as tobacco smoke). The discovery of both dominant3

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and non-dominant genetic changes associated with human disease has given us important clues about disease mechanisms, while experimental animal models provide the opportunity to test these pathways and identify non-genetic risk (or protective) factors.
Extensive research in humans and animal models has demonstrated a feature sharedby many neurodegenerative disorders (including AD, PD, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington’s disease): the accumulation of misfolded endogenous proteins seems to play a key role in synaptic dysfunction and neuronal cell
death [4]. Some of these proteins are also capable of acting as “seeds” for aggregation andspreading of disease in the nervous system [5]. Increased formation or decreased clearanceof these abnormal proteins may explain why ageing is a major risk factor for many of these
diseases [6]. This recognition of misfolded and aggregating proteins has created a whole
new strategy for new therapies (e.g. immunotherapy against -amyloid). The availabilityof rapid and sophisticated screening systems also now enables scientists to test large numbers of candidate drugs that might bear the promise of halting or even reversing the progression of neuropathology.
The enthusiasm generated by these advances in knowledge and technology has been
dampened significantly by the failure of clinical trials to demonstrate convincing efficacy
and acceptable safety outcomes in humans. This low yield, together with the hefty cost of
running large, long duration trials have become a disincentive to investment by the pharmaceutical industry. The reasons for the persistent lack of success in “translating” promising laboratory findings into real patient benefit have stimulated much discussion [7].
One priority identified is the need for better biomarkers. There is general consensus thatvalidation of biomarkers (for example, changes in cerebrospinal fluid chemistry, or new
brain imaging modalities) will provide a more sensitive and rapid way to monitor diseaseprogression and response to intervention. Furthermore, certain biomarker patterns mayhelp identify the patient subgroups most likely to benefit from specific interventions.
These general themes will now be discussed in the context of Parkinson’s and Alzheimer’s diseases.

Parkinson’s Disease

Two major discoveries have driven PD research in new directions over the past decade,and have in fact established a new paradigm of the disease itself. The first of these turning points was discovery of the importance of α-synuclein in this disease. This started
with the 1997 report of autosomal dominant parkinsonism arising from a single pointmutation in the gene for α-synuclein [8], followed quickly by the demonstration thatα-synuclein represents a major component of Lewy bodies and Lewy neurites (the intraneuronal inclusion bodies described by pathologist Friedrich Heinrich Lewy decadesago), in sporadic, “idiopathic” PD [9]. Further evidence of the importance of this protein
in disease pathogenesis was found in rare genetic cases of parkinsonism associated withmultiplication mutations of the α-synuclein gene; in these cases, just the increased expression of normal, non-mutated α-synuclein has a toxic effect [10]. These findings havespurred new lines of research aimed at answering a broad spectrum of intriguing questions, including:• What is the normal function of α-synuclein?
• How do genetic and environmental factors affect the levels, post-translational modification and degradation of α-synuclein?
• Under what circumstances is α-synuclein toxic to neurons, and by what mechanism?
• Are certain α-synuclein species a viable biomarker of disease status?
• Is this protein a promising target for pharmacologic intervention?
Genome-wide association studies have also identified other proteins and pathways thatlikely play a role in the pathogenesis of PD, such those involved in inflammation, oxidative stress and glucocerebroside metabolism [11]. How these other pathways are connectedto α-synuclein and neuronal death is an active area of investigation.
A second key discovery has emerged from the systematic analysis of the distribution of
α-synuclein inclusions in brains of persons who died with PD. In fact, these inclusions
seem to spread in a pattern that matches the general progression of the classic clinical PD
manifestations, from motor signs to the later onset dementia that occurs in most casesof advanced disease [12]. There is interesting evidence that α-synuclein may in fact spreadfrom cell to cell, via a process of seeding and propagation of aberrantly folded protein [13].
A fascinating recent finding is that abnormal α-synuclein aggregates can also be observedin the peripheral nervous system, such as the intestinal plexi, even in individuals withlimited brain pathology [14]. This finding correlates well with recently emerging recognition that the traditional diagnostic features of PD (tremor, bradykinesia, rigidity, postural instability) focus on the consequences of nigrostriatal degeneration, and fail to encompass the multi-neurotransmitter, systemic nature of the disease process. In fact, PD patients quite commonly suffer from a variety symptoms reflective of disturbances of sleep
and autonomic nervous function [15] that are often present early in the disease course. The
new paradigm of PD as a “whole body” disease, perhaps even one that starts outside the56central nervous system and could be diagnosed in a premotor phase, offers exciting prospects for understanding the root causes of disease.
New approaches to preventing, recognizing and treating PD are sorely needed. Current
diagnosis, and distinction of PD from other forms of parkinsonism, is based on motoric (movement) signs and symptoms and can be challenging even for movement disorderspecialists [16]. The pharmacologic cornerstone of PD treatment remains dopamine replacement therapy, which does offer symptomatic relief of motor dysfunction but overtime is associated with disabling adverse effects, including dyskinesias [17]. Deep brain
stimulation can also offer substantial relief from motor symptoms and reduce the needfor dopaminergic therapy. However, neither of these treatments provides a neuroprotective benefit that delays worsening motor impairments and prevents further disabling
manifestations such as falling and dementia. Cell replacement therapy has met with variable success, and unfortunately the transplanted cells also seem to acquire synucleinopathic changes over time [18].
The lack of disease-modifying therapy represents the most significant unmet need in thecare of PD patients [19]. A number of clinical trials, designed to test agents with soundbiologic rationale for neuroprotection (e.g. monoamine oxidase inhibitors and antioxidants), have been unsuccessful and difficult to interpret. Another, much debated example has been glial-derived neurotrophic factor, which despite promising results in bothrodent and primate models has yielded inconclusive results in human trials [20]. It is notclear that the agents being tested are truly ineffective. Rather, fundamental questions
concerning the trial designs have been raised, including:• Are the interventions being tested in patients with too-advanced disease? How can earlier stage disease cases be identified, when traditional diagnostic methods are imprecise?
• How can disease-modifying benefit be clearly distinguished from symptomatic benefit,
or even placebo effect?
This latter issue has led to the development of novel trial designs, such as the delayed startmodel used in the ADAGIO trial of rasagiline [21]. Interestingly, in this trial a dose of
1 mg/day met the endpoints consistent with a disease-modifying effect, over a 72 weeklong trial period, but 2 mg/day did not. One explanation for this finding is that the UPDRS rating scale as outcome measure is in fact not ideal for the measurement of progression in early disease [19]. Having access to more refined and sensitive markers of diseasestatus and change would certainly boost the power of prevention and treatment trials,
and a variety of promising new biomarkers is under current investigation [22].

Alzheimer’s Disease

A similar contrast between research progress and translational challenge is apparent in
the AD field. The discovery of the genetic underpinnings of early onset, autosomal dominant AD (mutations or duplications in amyloid precursor protein genes, or mutations in
the presenilin genes encoding part of the γ-secretase complex) and genetic risk profiles associated with ApoE and Down’s syndrome have catalyzed research into the mechanismsof sporadic disease [23]. The major protein components of the hallmark neuropathological findings in AD brains were identified in the mid-1980’s: β-amyloid (Aβ) in extracellular plaques/vascular deposits and tau in intracellular neurofibrillary tangles. The normal role of these proteins in neuronal physiology is still being defined. Transgenic animalmodels of cerebral amyloidosis and tau pathology have been generated to explore how
Aβ and tau are involved in neurotoxicity, and to search for candidate therapeutic agents
aimed at these targets.
Genetically modified mouse models have provided striking evidence that misfolded amyloid protein can spread into the central nervous system even if injected peripherally [24].
(This has led to AD been called a “prion-like” disease, however evidence of prion-like infectivity that permits transmission between animals or humans lacking). Tau aggregates
spread along neuronal tracts in a manner that closely resembles the spatial and temporal progression of AD in human brain [25]. However, although amyloid and tau pathology can be produced in these models, neuronal loss is often fairly limited and behavioral deficits do not correlate consistently with the status of plaques and tangles [26]. Theremay even be significant differences in plaque chemistry between species, since plaques in
the mouse model are not well labeled by the PET imaging ligand PIB used in humans [27].
Just as for PD, there are open questions about how predictive these animal models are forsporadic human AD, in which the gradual neurodegenerative process is likely perpetuated by a complex interaction of genetic and environmental factors, influenced by co-existing health conditions such as vascular disease, metabolic syndrome and ageing/frailty[28]. More research is needed to confirm key aspects of the amyloid hypothesis of disease,including identification of neurotoxic Aβ species, and how Aβ is linked to tau in the neurodegenerative process.
Despite the many unknowns about amyloid’s role in AD, drug trials have mostly aimed at
reducing Aβ production or increasing its clearance. Neuroprotective treatment is urgently
needed; the currently available therapy (based on inhibition of acetylcholinesterase or antagonism of NMDA receptors) can offer only modest benefit with regard to cognition andfunction [29], but does not slow cell death and brain atrophy. Unfortunately, despite mas-

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sive investment in clinical trials during the past decade, drugs that seemed highly promising in preclinical testing have failed, either because disease-modifying efficacy could not
be demonstrated, or due to the emergence of unanticipated adverse effects such as skincancer (with semagacetat, a γ-secretase inhibitor), meningoencephalitis and vasogenic
brain edema (noted with active and passive immunization, respectively) [30], [31]. The results of several ongoing passive immunization clinical trials that include standard clinicalendpoints plus some biomarker outcomes will become available in 2012. Drugs that target pathways other than amyloid (such as intracellular tau aggregation) are also being evaluated.
The dearth of clinical trial success has discouraged large-scale industry investments inclinical dementia research, and has prompted a spirited debate about the reasons for failure and how to address them. Questions that persist include:• How well do current animal models correlate with sporadic human AD processes –are the key pathogenetic mechanisms known, and are relevant drug targets engaged at
effective dose levels?
• Was the power of the studies limited by underlying disease heterogeneity among enrolled subjects and/or lack of stratification in study analysis?
• Did these trials enroll participants with too-advanced, irreversible disease?
• Are better outcome measures available that enable more precise measurement of diseaseprogression (or prevention of progression), over a shorter trial period?
Although the clinical intervention trials have not yet proven successful, a large amountof new biomarker evidence arriving from cross-sectional and longitudinal studies is now
defining the mechanistic and temporal continuum of AD progression. It has become
clear that Aβ accumulation in the brain begins at least ten years before the appearanceof dementia symptoms; even as this “preclinical” stage evolves, biochemical markers (e.g.
CSF Aβ-42 levels), brain images (radioligand binding of Aβ, diffusion tensor imaging)and sensitive neuropsychological tests show the development of altered brain physiology
and network dysfunction. Increasing synaptic loss and neuronal injury are accompanied
by increased cerebrospinal fluid tau and phosphorylated tau levels as well as structural(regional volumetric loss) and functional (hypometabolism) brain imaging patterns [32].
Further research is needed to clarify the interactions between the initiating disease pathways and subsequent adaptive or maladaptive response mechanisms. For example, amyloid
accumulation is a common feature of the aged human brain, but not consistently associated with progressive cognitive decline [33]. It is possible that events downstream of initialamyloid toxicity are involved in the transition from synaptic dysfunction to increasingly
irreversible changes in plasticity and structure, such as epigenetic blockade [34].
While the performance characteristics of new biomarkers are not yet fully characterized(especially in healthy ageing populations), these studies have provided a basis for defining the symptomatic predementia phase of AD in a systematic manner [35],[36]. These new
constructs of mild cognitive impairment (MCI), and even earlier “pre-MCI amyloid accumulation”, will facilitate the identification of cohorts in which interventions can betested at an earlier disease stage, presumably when disease modification is more readily achieved. Improved understanding of how AD pathology starts, and the factors thatdrive disease progression and compensatory mechanisms, will also serve the testing of effective non-pharmacologic interventions. In fact, there is emerging evidence that physical activity and specific cognitive training and exercise can yield objective and potentially neuroprotective benefits [37],[38].

Improving Translation

There is strong general agreement about the priorities for the next phase of neurodegenerative disease research and translation. First, improved in vivo and in vitro preclinicalmodels must be developed, particularly models that can be used to assess more complex,“multiple-hit” hypotheses of pathogenesis. Such tools could also be employed to discover new biomarker profiles, explore mechanisms of neuroprotection and identify pharmacologic agents with higher probability of efficacy. New technologies in genetic/epigenetic
manipulation and RNA interference are highly promising, as is the use of induced pluripotent stem cells derived from patient fibroblasts [39], a technique that produces a “human disease in a test tube” model amenable to screening new drug candidates.
A second research priority is clearly the validation of biomarkers. Validation of markers inlongitudinal cohort studies can help us distinguish healthy ageing mechanisms from thosethat drive disease initiation and progression. Biomarkers can improve our ability to diagnosis earliest stages of disease with accuracy and improve clinical study quality by refining
patient selection criteria and analytic power. They can enable us to design shorter, proofof-concept clinical trials to demonstrate drug-target engagement and physiologic effect.
Finding and validating “ideal” biomarker profiles is a daunting and expensive undertaking that requires the concerted efforts of all stakeholders. A number of exciting academicindustry consortia, endorsed by patients and advocacy groups, have been established to create standardized methods and share data, such as the Alzheimer’s Disease Neuroimaging

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Initiative [40] and the Parkinson Progression Marker Initiative [41]. An EU Joint Programme – Neurodegenerative Disease Research has also been launched, with biomarker
studies a primary focus of its first funding call [42].
Finally, it is important to note that effective translation is not limited to the “bench to
bedside” flow of information. In fact, findings in clinical and epidemiologic studies constitute the “bedside to bench” half of the feedback loop, ensuring integration of the “human model” results into laboratory study design. Nor should translational research belimited to drug discovery and secondary prevention therapies. Application of evidencebased primary prevention strategies could have a profound impact on disease prevalenceand socioeconomic burden [43]. And, for patients with advancing disease, there is muchto be learned about how to preserve autonomy and quality of life in both home and institutional care settings. Neurodegenerative disease research and care can pose important
ethical questions that must be considered in a culturally sensitive way. Research institutions and collaborative networks that embrace a multi-disciplinary approach to the challenge of neurodegenerative disease will be best poised for true translational success.

Presentations

Ageing without Alzheimer’s Disease:
The Challenge of the Next Four Decades
Konrad BeyreutherLife expectancy around the world has increased steadily for nearly 200 years. Improvements in sanitation, housing and education caused a steady decline in early and mid-life
mortality, which was mainly due to infections. This trend continued with the development of vaccines and the antibiotics causing a decline in late-life mortality. Why life expectancy continues to rise and where and when this process might end remains obscure.
This is something we need urgently to discover because if this trend continues Alzheimer‘s disease (AD) becomes a major health problem in the next four decades. Given thepredicted increase of ten years in life expectancy by 2050, there will be at least a triplication in the number of patients with AD worldwide from 35.6 to 115.4 million. The estimated worldwide annual cost of care for patients with AD and other dementias will increase from estimated US $ 604 billion in 2010 to 1.8 billion in 2050. We need to be prepared to effectively treat patients with AD and to postpone the onset of symptoms inindividuals at risk in order to prevent the vast increases in AD patients. The challenge fortreatment is to compensate for the neuronal loss. The challenge for prevention is to postpone the onset of AD by ten to eleven years, because after age 60 the prevalence of AD
doubles roughly every five and a half year of age.
How can this be achieved? Looking ahead, it seems unlikely that the ageing process itself
will be abolished any time soon. Given that ageing is driven by random damage of molecules, cells and organs, there must be a considerable overlap between the underlying causative pathways of age-related chronic diseases such as AD, cardiovascular disease, cancer
and diabetes. As revealed by demography, this seems to be the case and changes in lifestyle seem to slow down the rate at which age-associated damages accumulate and diseases progress.
With regard to AD, it has recently been suggested that up to half of all cases worldwide
are potentially attributable to seven risk factors. All of these can be influenced by lifestyle. What causes the other half of AD cases remains obscure. However, as suggested by genetics and epidemiology, brain cholesterol homeostasis and inflammation may
be among the other key players. Appropriate approaches to unravel these and other unknown links between ageing and AD requires the study of interactions between all components of the human biological system. Only by systematically probing the complex
mechanisms underlying ageing and most if not all of its associated diseases can we transform our dramatic past success in postponing death into a future without symptomat-

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ic AD. In this context, it needs to be emphasized that worldwide scientific collaboration
is an important factor because collaboration, an important indicator of competitiveness,enhances the quality of research, improves its efficiency and effectiveness, and is increasingly necessary as the scale of both budgets and research challenges grow.

Exploration into the Molecular Mechanisms Underlying
Parkinson’s Disease Using Medaka Fish Models
Ryosuke Takahashi [44]Parkinson’s disease (PD) is the second most common neurodegenerative disease among
elderly people. The major clinical features of PD are motor disturbances such as tremor,
rigidity and akinesia that are caused by selective dopaminergic cell loss in the substantia
nigra in the midbrain. Regarding the etiopathogenesis, exposure to toxins and genetics
are thought to constitute the main determinants in the onset of PD. Although model animals including mice, Drosophila and nematodes have been used to recapitulate the clinical and pathological features of PD through exposure to neurotoxins or gene manipulation, highly successful models are yet to be obtained.
The medaka fish, Oryzias latipes, is an emerging vertebrate model with several unique advantages. The genome size of medaka is relatively small, i.e., around 800Mb, and genome
sequencing has been completed. Moreover, genetic engineering methodologies such as
mutagenesis and transgenic techniques have already been established. Furthermore, they
are easy to maintain at low costs. Recently, we have established neurotoxin and gene mutagenesis-based models of PD in medaka fish.
Treatment of medaka at the larval stage with 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), a classical dopaminergic neurotoxin, decreased the number of dopaminergic cells in the diencephalon and reduced spontaneous movement, which is reminiscent of human PD patients and other MPTP-induced animal PD models. Among
TH(+) neurons in the medaka brain, only a specific cluster in the paraventricular areaof the middle diencephalon corresponding to the substantia nigra of mammals was vulnerable to MPTP toxicity. Taking advantage of the ease of accessibility of the cerebrospinal fluid (CSF) in fish, we injected proteasome inhibitors, lysosome inhibitors and endoplasmic reticulum (ER) stress inducers into the CSF space of medaka. In all these cases,
selective dopaminergic and noradrenergic cell loss was observed. Furthermore, treatedfish exhibited reduced spontaneous movement. Treatment with these compounds also

induced the formation of inclusion bodies resembling Lewy bodies, which are characteristic of PD. These results suggest that disturbances of proteolytic systems and ER stress
may contribute to the pathogenesis of PD.
Study of the genes responsible for familial PD have significantly contributed to the understanding of the molecular pathogenetic mechanisms underlying PD. Recently, we havesucceeded in establishing models of an autosomal recessive form of PD termed PARK 6
in medaka by screening of TILLING library. PINK 1, the gene responsible for PARK 6,
encodes a putative protein kinase localized in the mitochondria. PINK 1 null mutant
medaka did not display neurodegenerative phenotype. However, they showed a significant decrease in spontaneous movement during the late stages of life as well as downregulation of dopamine metabolism. We have also established medaka models for PARK 9,another autosomal recessive familial PD. PARK 9 model displayed dopaminergic neuronal degeneration with functional and morphological lysomal abnormalities. These datasuggest that PARK 9 may be caused by lysosomal dysfunction. The medaka fish model provides excellent opportunities to dissect the molecular mechanisms underlying PD.

Ageing and Neurodegeneration: What’s Next?
Pierluigi Nicotera

The ageing demographic of society poses an enormous challenge to both industrialized
and non-industrialized countries. While it is clear that ageing represents a major common risk factor for many diseases, including AD and PD, the underlying biologic mechanisms remain to be defined. For example, caloric restriction is well known to delay ageing by years in non-human primates. The mechanisms by which nutrient status can affectlifespan so dramatically has been investigated in animal models such as Caenorhabditis
elegans. In this worm model, DZNE scientists have demonstrated that longevity is modulated by WAH-1 (AIF homologue) signaling pathways that link oxidative stress, mitochondrial activity and autophagy. From a mechanistic standpoint these ageing investigations seem to be directly relevant to similar findings in models of neurodegenerative disease. However, although relatively simple animal models serve the purpose of defining
mechanistic pathways and potential therapeutic targets, they will not suffice to answer
the more complex question of how to extend the length of healthy, high-quality life for elderly people.

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Another missing piece of the puzzle is elucidation of the biologic underpinnings of cognitive reserve, or the resilience of brain in maintaining cognitive function despite progressive damage. This may be achieved through recruitment of alternative networks andthus research into synaptic plasticity is of key importance. Recent data obtained fromtransgenic animal studies in our laboratories have provided insights into the dynamics
of dendritic spine morphology and synaptic connectivity, regulated by non-coding microRNAs such as mir29. There is also accelerating interest in the role of inflammationand immunity (both innate and acquired) in neurodegeneration. We must press forwardwith fundamental research on multiple fronts, even as we apply early findings to translational initiatives such as new target screening technologies and biomarker discovery.
Finally, it has become increasingly clear that innovative models of cooperation between
academia, industry and governmental agencies are needed to make efficient headway
against the challenge of neurodegenerative disease. The traditional clinical trial model(large, long-term studies, relatively insensitive endpoints) has not yielded effective treatments for neurodegenerative disease. Validation and regulatory acceptance of biomarkers correlated with disease pathogenesis and progression will enable a much more efficient process of small proof-of-principle trials of promising drug candidates. One newmodel of cooperation is being developed in Germany, where the German government isestablishing national health centers, including the DZNE which is specifically focusedon neurodegenerative disease research. Founded in 2009, the DZNE now employs over
400 scientists, working across the entire spectrum of translational investigation. Theinteraction of fundamental, clinical, population and health care system research disciplines offers exciting opportunities for new insights and approaches. A program of active collaboration national (industry, insurance, academic and governmental) and international partners has been launched. The DZNE would welcome the opportunity to extend its research network to Japanese partners in the near future.

Molecular Mechanisms Underlying Initiation of Development of
Alzheimer Disease and Therapeutic Strategy
Katsuhiko Yanagisawa

A great deal of effort has been made to develop strategies to prevent and treat Alzheimer
disease (AD); however, there is still no cure for the disease. Although the development ofsymptomatic treatments has been partly successful, development of disease-modifying
drugs has not succeeded yet. It is likely that the clarification of early and specific molecular event(s) in AD is a prerequisite for the development of bona fide drugs that suppress
the emergence and progression of the disease. Several fundamental questions about theamyloid cascade hypothesis, which is widely accepted and supports anti-amyloid therapies, have not been satisfactorily answered. For example, it remains to be clarified why
and how Aβ assembles and deposits in the brain only in region-specific and age-dependent manners.
To elucidate these issues, we previously examined human brains with or without AD pathology and identified a unique Aβ species, which was characterized by its tight binding to a ganglioside (GM1), specifically in membrane fractions prepared from humanbrains in the early stage of AD. On the basis of the molecular characteristics of the ganglioside-bound Aβ (GAβ), including its high potency to facilitate assembly of soluble Aβ
and its altered immunoreactivity, we hypothesized that Aβ adopts an altered conformation through its binding to ganglioside, and then induces Aβ assembly into amyloid fibrils by acting as a seed. To date, various in vitro and in vivo studies on GAβ have been
performed and have revealed how Aβ preferably binds to gangliosides, i.e., what are thefavorable physicochemical and neurobiological conditions for GAβ generation, and whatis the pathological significance of GAβ-dependent Aβ assembly in the development of
AD. Notably, GAβ is favorably generated in unique ganglioside-clustered, raft-like membrane microdomains. The membrane microdomains, which are responsible for GAβ generation, were characterized using synaptosomes and non-synaptosomes prepared frommice of different ages. Interestingly, the membrane microdomains with a high potency
to induce Aβ fibril formation through GAβ generation predominantly appeared in anage-dependent manner specifically in synaptosomes but not in non-synaptosomes. Furthermore, high-density ganglioside clusters, which were specifically recognized by a novel peptide p3, were detected specifically in synaptosomes prepared from the aged mousebrains. Currently, it remains to be clarified how the ganglioside clustering is induced in
the brains that are prone to harbor Aβ deposits; however, it has been suggested that lipid
molecules other than gangliosides in the raft-like, membrane microdomains, such as cholesterol and sphingomyelin, are involved in the process.

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The GAβ hypothesis may also explain why Aβ deposition occurs only in a region-specific manner. In regard to this issue, we previously focused on hereditary variant-type Aβs
because these Aβs deposit in the brain strictly in a region-specific manner as follows. The
Arctic-type Aβ exclusively deposits in the brain parenchyma whereas the Dutch-type Aβ
predominantly deposits in blood vessel walls. On the basis of the assumption that GAβ
plays a crucial role in the initiation of Aβ assembly, we examined the possibility that local gangliosides are responsible for the regional specificity of Aβ deposition by incubating the variant-type Aβs in the presence of various ganglioside species. Interestingly, theAβs preferentially and significantly assembled into fibrils in the presence of particular
gangliosides: the Arctic- and Dutch-type Aβs require GM1 and GM3/GM2 gangliosides, respectively, for their assembly. Furthermore, GM1 and GM3/GM2 gangliosides
were selectively expressed on the surface of presynaptic neuronal membranes and vascular smooth muscle cells where Aβ deposition starts to form amyloid in the brain parenchyma and blood vessel walls, respectively.
To apply our findings on GAβ to the development of disease-modifying drugs for AD,
we have performed molecular dynamics of the interaction between Aβ and the sugar
chain of gangliosides. On the basis of the successfully defined GAβ structure, screening in silico from chemical libraries to obtain candidate compounds is now in progress.

Therapeutic Strategies for Treatment of Alzheimer’s Disease:
Challenges from a Drug Discovery Perspective
Bernd Sommer

Alzheimer’s disease is characterized by progressive memory loss, a decline of perceptualand intellectual abilities and the ultimate loss of personality. A definite diagnosis is only
possible post mortem. It is the most abundant form of dementia and patient numbers are
expected to increase two- to three-fold by the year 2050. Currently available therapies
show only limited efficacy in improving daily living performance. Therefore new medications which improve functional performance and slow down disease progression are urgently needed.
The discovery efforts towards new treatment approaches have been guided by neuroanatomical mapping of affected memory domains, an increase in mechanistic understanding of processes underlying synaptic transmission and plasticity as well as findings from
pathology and genetic analysis of the disease. New avenues pursued to improve synap-

tic function of demented patients focus on targets along the glutamatergic transmission path, a system shown to be significantly impaired in Alzheimer’s disease. Numerous
drug candidates acting along this pathway have been identified, which increase synaptic
strength and improve memory function in preclinical models, however clinical proof ofconcept for these new mechanisms of action is still elusive.
The amyloid β cascade hypothesis as the dominant concept for new disease-modifying
approaches emerged about two decades ago and has been continuously supported bystrong evidence from disease pathology, human genetics and preclinical models. A plethora of approaches targeting brain amyloid β by reduction, clearance or inhibition of its
production is being pursued by pharmaceutical industry with the most advanced projects being in late stage clinical development. Nevertheless also for these projects a clinicalproof of concept has not been obtained to date.
Therefore, from a patient’s perspective, the history of drug development in Alzheimer’s
disease must appear sobering. In the past 20 years more than 50 compounds entered clinical phase 2 or later, yet only five drugs are approved for the treatment of Alzheimer’s disease and none of the clinical candidates in phase 3 has delivered a proof of concept. This
lack of clinical proof of efficacy mirrors a general trend in pharmaceutical drug development namely the increasing number of project terminations in late stage development,
indicating an insufficient predictivity of preclinical results for clinical outcome. Consequently, major efforts are required to identify and improve translational approaches andmethodology which can bridge the gap from bench to bedside.
Such efforts must include the identification and validation of suitable biomarkers to enable a more precise demonstration of drug engagement with the target and better guidance for clinical dose selection to aid better patient stratification or to measure diseaseprogression. Furthermore the revision of clinical assessment tools and the alignment
with preclinical readouts may provide a basis for better predictability of new drug concepts. In fact, new imaging technologies such as structural MRI or PET with amyloid
specific tracers as well as biochemical markers such as the amyloid β peptide and the tau
protein or phospho-tau are being qualified as biomarkers, and offer already a promisingbasis for better prediction of drug efficacy at earlier time points. Similarly, neuropsychological tests based on non-verbal performance (such as CANTAB ) are being employedin analogous set-ups for clinical trials and preclinical tests with the aim to improve predictability.
These biomarker studies have already provided evidence that relevant pathologicalchanges start much earlier than Alzheimer’s disease is currently diagnosed with regulatory accepted outcome measures. This imposes a high failure risk on new treatment ap-

17

Presentations

18

proaches in clinical trial designs beyond a point of no return and urgently asks for a revision of disease taxonomy and regulatory adaptation.
Authorities are now beginning to recognize this challenge and revise their guidelines.
Recommendations for criteria to define earlier stages of disease definition are being
elaborated. Nevertheless, it will require large continuing efforts across disciplines andboundaries with intense dialogues between preclinical and clinical researchers and regulatory authorities to overcome these challenges for the benefit of future patients.

Cognitive Ageing versus Dementia: When to Relax, When to Worry?
Gereon Fink

The steady increase in life expectancy and associated predicted rise in dementia prevalence pose substantial socioeconomic challenges. The increase in life expectance currently averages 12 months every five years and shows no sign of abating. For example, thenumber of Europeans aged 65 and over is expected to increase by 45% between 2008 and
2030, and will be over 30% of the population by 2060. Unfortunately, the risk of developing dementia also doubles with increasing age: while those ranging from 65 to 69 years
suffer a 2% risk of developing dementia, those aged 90 -95 years have a 35% risk. Furthermore, as long as the key neurodegenerative processes remain to be further elucidated inorder to develop novel causal treatment strategies, an as early as possible diagnosis of subjects at risk is important. The latter necessitates that normal ageing associated cognitive
decline can be differentiated from mild cognitive impairment (MCI) associated with anincreased risk of conversion into dementia. Likewise, a better definition of subjects at risk
may help to allocate available symptomatic treatment to those who benefit most. In fact,
major reasons for the failure of clinical trials include too-late intervention and non-specific subject selection criteria.
Increasing chronological age is associated with brain frailty, reflected in increases in error rates and test completion time in neuropsychological assessments. Stress and ApoEε4
status also have negative impacts on memory retrieval ability in older persons. “Mild cognitive impairment” exists when significant impairment of episodic memory is present(without altered activities of daily living or other cognitive impairment). This diagnosis
is significant because 75% of MCI patients will progress to dementia over a five-year period (although, importantly, 25% will not). To date no single biomarker (including structural and functional MRI and PET imaging, cerebrospinal fluid analysis) has been doc-

umented to be sufficiently sensitive and specific to identify the earliest MCI stages thatwill evolve into dementia, but combinations of such markers may do so. Recent studies suggest that some interventions might delay the progression of early cognitive dysfunction (e.g. donepezil in ApoEε4 carriers, exercise), and should be investigated further
utilizing carefully selected and phenotyped subject populations. The emerging data allow further insights into the neurobiology of normal ageing and the neural pathomechanisms underlying mild cognitive impairment.

The Challenges in Genomics: Exploration into Better Understanding
the Molecular Basis of Neurodegeneration
Shoji Tsuji

During the past three decades, we have witnessed remarkable advances in our understanding of the molecular basis of hereditary neurodegenerative diseases, which havebeen accomplished by “positional cloning” strategies started in early 1980s. The discoveries of the causative genes for hereditary neurodegenerative diseases accelerated not only
the studies on the molecular mechanisms of diseases, but also the studies for development of disease-modifying therapies based on the molecular mechanisms of diseases.
To elucidate the molecular basis for sporadic diseases, genome-wide association studies(GWAS) based on the “common disease-common variants hypothesis” have been undertaken to identify the disease-relevant alleles. Although GWAS has successfully revealed
numerous disease-susceptibility genes for neurodegenerative diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. In contrast to these observations, substantially high λs, an estimationof recurrent risks for siblings of affected individuals, have been demonstrated in sporadic neurodegenerative diseases, including Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis.
We have recently learned that the effect size of the disease-relevant alleles that are identified by comprehensive resequencing of GBA of large data sets of cases of Parkinson disease and controls are substantially larger than those identified by GWAS[45], [46]. Thesefindings strongly argue for the role of the “common disease-multiple rare variants hypothesis” in identifying disease-susceptibility genes for sporadic neurodegenerative diseases. To identify disease-relevant alleles based on the “common disease-multiple rarevariants hypothesis”, however, comprehensive genome sequencing is required[47].

19Presentations

20

Given the rapidly improving technologies of next generation sequencing (NGS), it has
become possible to apply comprehensive genome sequencing to identify disease-relevant alleles with large effect sizes. To accomplish this aim, we have very recently established Medical Genome Center as a core facility at the University of Tokyo Hospital.
This center is being designed to produce 1,500Gb in two weeks. In a single personal genome, there are more than 3,000,000 variations. Thus, “genome informatics” is becoming a challenging field in the personal genome analysis. In our Medical Genome Center,a strong interdisciplinary research team consisting of specialist in neurology, clinical genetics and genome informatics has been organized. We are currently applying the comprehensive resequencing of human genome to elucidate the disease-relevant alleles to elucidate the molecular basis of sporadic neurodegenerative diseases based on “common disease-multiple rare variants hypothesis”. We are also planning to apply these technologies
for the clinical practice in the near future.

A New Culture of Responsibility: Science, Ethics andthe Challenges of Neurodegenerative Disease
Dieter Sturma

The diagnosis and treatment of neurodegenerative diseases, particularly those causing
psychiatric disorders and dementia, pose severe challenges across a wide spectrum of issues, including medical, research, economic, political, ethical, moral and legal problems.
These issues should be considered in the context of the life of persons over time, within which certain groups such as the very young and persons with cognitive impairment(in the case of dementia, “disappearing subjects”) are – at least in the realm of politicaldecisions – underprivileged compared with active, autonomous adults. Alzheimer’s andother dementing diseases present particularly complex decision scenarios: If disease risk
can be demonstrated with new biomarkers decades before symptom onset, and with little preventive therapy to offer, how should that risk be communicated to individuals? As
cognitive impairment appears and progresses, how are informed decisions made about
participating in research or receiving care? What are the key determinants of quality oflife for a person with advanced dementia–lacking understandable linguistic expression
and a sense of self over time?
Adherence to a framework of bioethical principles – such as autonomy, beneficence, nonmaleficence, and justice – and the use of bioethical methods allow for a recognition ofdifferent hierarchies of values and grounds for reasonable disagreement, beyond dogmatism and fundamentalism. In accordance with these principles a standard of living adequate for the health and well-being is considered a human right, which covers medicalcare and necessary social services for persons of old age. The bioethical principles set clear
limits to a priority of cost-benefit-considerations in the field of medical research, therapy and care. The bioethical principles do not guarantee the right to all forms of medical
treatment. In a health system burden and benefit have to be in balance. No generation
or social group can be expected to bear a disproportionate burden. The determinationof what can count as a disproportionate burden varies depending on the socio-economic context. For instance, the increase of social contributions and health expenses needs tobe put in context with the general improvement in living standards and the constantly
rising level of medical care.
A new culture of responsibility needs to be established when it comes to dealing withneurodegenerative diseases. This culture should be able to increase ethical sensitivity ineveryday life, to revise our conventional notions of personal identity and to set responsibility, autonomy, paternalism, and care in a reasonable relation to each other. Finally, we need to inquire more deeply into the difference between normal ageing and pathological decay. There is already a culture of responsibility for early stages of human life,
which is established both, ethically and legally. Corresponding regulations for later stages of life can be found in legislation, but are missing in the social realm. Objectives of the
new culture of responsibility should include: a) a new understanding of the life of persons over time, b) an extended responsibility for the entire life (in the first and third person perspective), c) the recognition of different life plans in later stages, d) the formationof a profound intergenerational and intragenerational balance, e) new guidelines for research ethics in the event of declining cognitive capabilities of probands and patients,and f) an improvement of medical research and care for the late stages of the life of persons.

21Panel Discussion and Comments from the Audience

22

The DWIH Tokyo and the DZNE welcomed approximately 100 participants from academia as well as health care and industry organisations to the German-Japanese Symposium on Ageing and Neurodegeneration.
The two countries share many pertinent similarities which make collaboration in thearea of neurodegenerative disease compelling: international leadership in science andtechnology, excellent health care systems and the challenge of an ageing population susceptible to dementia and other chronic neurologic disorders. The symposium was an opportunity to find new approaches and collaborations for translational research linking
academic and industry partners. The two major themes covered by the symposium wererecent research advances and directions, and social and ethical dimensions of ageing andneurodegeneration.
The productive and stimulating discussion focused on challenges and new ways to facilitate collaboration between Germany and Japan, across academia, industry, and regulatory parties.

Recent Research Advances and Directions in Germany and Japan• It was suggested that in addition to new drug targets, the repositioning of drugs developed for other purposes might prove valuable. Examples cited include an anti-epileptic
agent with efficacy in PD and an anti-diabetic drug with potential neuroprotective effects. The interest in utilizing high-throughput screening as a means to identify promising drug candidates was expressed, although the compound libraries needed for such investigations are extremely expensive.
• It was agreed that the repositioning of drugs was one approach that might help identify
novel targets. At the same time, it was not expected that this would make a major impact.
A more viable approach would be to identify a pharmacologic agent’s efficacy at an earlier disease stage.
• Participants commented on the current situation of having insufficient data to guidetherapeutic trials, and advocated for academia and industry to identify common interests for collaborative work. It was noted that specific collaborative projects involving industry (including small biotechnology firms) and academia could be a mutually beneficial discovery avenue.
• Furthermore, it was stated that multi-disciplinary research was needed to overcome thecomplexity of overlapping risk factors and gene-environment interactions. Research into
health care approaches was also seen as important, but quite challenging given the differ-ences even between European countries with regard to care models and health data portability. The importance of non-competitive consortia in genetics research, and of studying non-coding DNA regions as well as coding variants was emphasized.
• There was general agreement about the need for clear rationale behind the selection of
specific in vitro or in vivo models for specific studies (cell death, cortical function, etc.),
whether studying basic pathogenetic mechanisms or screening new drugs.
• It was specified that the highest priority is to cut down the time and cost of clinical trials, by designing smaller proof-of-principle studies with better biomarkers. Also, a systems biology approach was needed to avoid over-emphasis on a multitude of individual drug targets.
• The bioethical difficulties posed by very early disease diagnosis were especially noted. At
the same time, participants were optimistic that development of the personal genome approach would lend insight into causes and optimised treatment.

Perspectives for Collaboration• It was noted that German-Japanese collaborations in the area of genetics research could
provide opportunities to address the challenge of evaluating the clinical significance ofsequence variations, by performing collaborative studies or networking large databases.
Fear of discrimination was seen as one obstacle to enrolling subjects in genetics studies inJapan. In Germany, on the other hand, there was general willingness to participate if it isclear how the genetic information is used.
• It was noted that a German-Japanese collaboration in the area of dementia researchwould be very rewarding, given for example the differences between the two societies
with regard to the concepts of dignity and the place of aged and disabled people in society. It was further specified that one fruitful area of collaboration could be in mixed ADvascular dementia, the prevalence of which is high in Japan.
• In discussion with the audience it was acknowledged that although clinical trials andhigh-throughput screening could be done more quickly in other countries, Germany andJapan could combine their strengths in careful research design and implementation (e.g.
precise patient stratification) as well as cutting-edge technology. Government funding
should be encouraged in particular areas such as new clinical/biological endpoints andsystems neurology.

23

Editorial Notes

24

Published by:German Research and Innovation Forum Tokyo (DWIH Tokyo)
Sanbancho KS Bldg. 5F, 2-4 Sanbancho,
Chiyoda-ku, Tokyo 102-0075
Tel: +81 (3) 5276 8820
Fax: +81 (3) 5276 8733
info@dwih-tokyo.jp
www.dwih-tokyo.jp
Editorial Team:
Editing: Dr. Sarah Jewell, Regine Dieth, Marijke Wahlers
Design, layout and lithography: Lisa Eidt
Printed in Japan
ISBN: 978-3-942600-08-8
Tokyo, October 2012

© DWIH Tokyo
The DWIH Tokyo is jointly organized by the German Rectors’ Conference (HRK) and
the German Chamber of Commerce and Industry in Japan. It is funded by the Federal
Foreign Office of Germany and supported by the German Federal Ministry of
Education and Research.

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LIST OF CONTRIBUTORSProfessor em. Dr. Konrad Beyreuther

Professor Dr. Dieter Sturma holds a chair

is Director of the Network Aging Researchof philosophy at the University of Bonn. He(NAR) of Heidelberg University, distin-is Director of the Institute of Science andguished senior Professor at Heidelberg

Ethics and the German Reference Centre

University and emeritus Professor offor Ethics in the Life Sciences at the Univer-

Molecular Biology at the Center for Molec-

sity of Bonn. He also heads the Institute forular Biology Heidelberg University (ZMBH).

Ethics in the Neuroscience at the ResearchCentre Jülich.

Professor Dr. Gereon Fink is Professorand Head of the Department of Neurology,

Professor Dr. Ryosuke Takahashi is

University Hospital Cologne, and Director

Chairman of the Department of Neurol-of the Cognitive Neurology Section of theogy of the Graduate School of Medicine at

Institute of Neuroscience and Medicine,

Kyoto University.

Research Centre Jülich. He is also First
Pro-Rector and Pro-Rector for Research

Professor Dr. Shoji Tsuji is Director of theand Junior Scholars at the University of

Medical Genome Center at The University

Cologne.

of Tokyo and Professor and Chair of the
Department of Neurology at The Univer-

Dr. Sarah Jewell, MD MPH heads the Sci-

sity of Tokyo.

entific Strategy Office of the German Center for Neurodegenerative Diseases (DZNE)

Dr. Katsuhiko Yanagisawa is Direc-

in Bonn.

tor of the Center for the Developmentof Advanced Medicine for Dementia andProfessor Dr. Dr. Pierluigi Nicotera is Sci-

Vice-Director of the National Center for

entific Director and Chairman of the Execu-

Geriatrics and Gerontology Research Insti-

tive Board of the German Center for Neuro-

tute in Nagoya. He holds a professorshipdegenerative Diseases (DZNE) in Bonn.

at Nagoya University Graduate School of
Medicine.

Dr. Bernd Sommer heads the discoveryof new therapies in the fields of CNS (Central Nervous System) diseases at the Boehringer Ingelheim group.

for German scientific and research interests in Japan. Its aim is to present German
research organisations and innovative companies in a concerted effort, thereby strengthening scientific and economic cooperation with Japanese partners.
The DWIH Tokyo is thus the central point of contact for Japanese and German researchorganisations, universities, and businesses or the interested public in general. At thesame time it supports and supplements the activities of the participating German organisations by providing information via its website, a comprehensive, subject-specific calendar of events and a number of jointly organised events.
The DWIH Tokyo has been set up jointly by the German Rectors’ Conference (HRK) and
the German Chamber of Commerce and Industry in Japan (GCCIJ) on the initiative of theFederal Foreign Office of Germany and the German Federal Ministry of Education andResearch.
www.dwih-tokyo.jp

German Center for Neurodegenerative Diseases (DZNE)
The DZNE was founded by the German government in 2009 as the first of six healthresearch centers focusing on the most challenging major diseases. DZNE is a multi-campus biomedical research center with the mission of discovering the causes of neurodegenerative diseases (including Alzheimer’s disease (AD) and other dementias, Parkinson’s disease (PD), amyotrophic lateral sclerosis and rare disorders), and developing
effective preventive and therapeutic interventions against them. Within just a few years
the DZNE has grown to nine centers (Berlin, Bonn, Dresden, Göttingen, Magdeburg,
Munich, Rostock/Greifswald, Tübingen, Witten) and over 500 members of staff. DZNE scientists are engaged in research investigations spanning a broad range of themes, including laboratory science, population studies, clinical science and health care systems
research. This multidisciplinary approach coupled with an active program of collaboration with industry and international partners is structured to create the synergy needed
to develop new and truly effective preventive and therapeutic strategies.
www.dzne.de

German-Japanese Symposium on Ageing and Neurodegeneration

The German Research and Innovation Forum Tokyo (DWIH Tokyo) and acts as an umbrella

12 December 2011 | Osaka, Japan

German Research and Innovation Forum Tokyo