LCPotential
Project co-ordinator Per Hammarström, of the Department of
Chemistry at Linköping University, discusses LUPAS – innovative
diagnostics and therapy for neurodegenerative diseases
Pan European Networks: Science & Technology
06
154
PROFILE
T
he European population is ageing. As a consequence, age-
associated neurodegenerative diseases such as Alzheimer’s
disease are on a steady rise, reaching epidemic proportions
of serious concern to the afflicted patients and their relatives.
These horrific diseases put a heavy burden on society, including a
decade of heavy dependence on care givers, culminating with care
at nursing homes. If this epidemic is not sequestrated it is
projected to threaten the core of the welfare societies of all
European nations. The culprit within these diseases is accumulated
misfolded protein molecules, called amyloids, which corrupt
normal cellular functions and cause disease. Amyloids are self-
perpetuating fibrillar states, which can hide for decades within
affected individuals and replicate with immense efficiency,
especially in the elderly.We, as a community, still stand short in
delivering definite diagnosis or benign disease-modifying treatment
or cure to any neurodegenerative disease. The only way to fight
these diseases is long-term, focused, high quality research.
The LUPAS project developed novel molecular agents and
methods for use within diagnostic imaging that relies on reporter
molecules based on luminescent conjugated polymers (LCPs).
The LCP molecules target the pathogenic protein aggregates with
high selectivity and specificity. Candidate lead molecules have
also been shown to have therapeutic potential.
Consortium
The LUPAS partners were assembled from a wide variety of areas
ranging from experts within organic synthetic chemistry, synthetic
nanochemistry, amyloid structure, prion disease‚ Alzheimer’s
disease, magnetic resonance imaging, multi-photon physics and
hyper spectral imaging. This group formed the critical mass of
competences needed to reach the project’s ambitious goals.
The partner organisations in the LUPAS consortium are: Linköping
University (Sweden), Université Claude Bernard Lyon 1 (France),
University of Tübingen (Germany), Norwegian University of Science
and Technology (Norway), Zürich University Hospital (Switzerland),
Charité Universitätsmedizin Berlin (Germany), Applied Spectral
Imaging (Israel) and Genovis AB (Sweden).
Results
LUPAS was a three-year focused research project under the
Seventh Framework Programme. Significant achievements were
reached, which is well reflected by a surge of interest from the
research community to use the LCP technology. Other indications
of success are the high citation rate of publications from the
LUPAS research groups. By combining the diversity of scientific
knowledge available within the consortium, progress towards the
development of multimodal amyloid ligands for non-invasive
imaging was achieved. The outcome affords visualisation of
dynamics and biochemical activity of pathological processes of
Alzheimer’s disease and prion diseases in real-time from the
molecular level to the organ and full body scale. Most importantly,
novel molecular insight regarding the pathological hallmarks of
these diseases and the specific chemical requirements for
optimal amyloid ligands was concluded.
LCPs are fascinating molecules that behave like structural
chameleons.When an LCP binds to its amyloid target, the LCP
changes shape. The LCP thereby also alters its colour depending
on the amyloid structure (Fig. 1). Hence it reports different
outcome signals which can be detected by a range of techniques.
Lead compounds were identified from a library. This procedure
selected LCPs with distinct chemical groups for detection and
spectral assignment of protein deposits in Alzheimer’s and prion
diseases. Amyloid structures are vastly heterogeneous. It is not
Fig. 1 The principle of LCP fluorescence markers for structural analysis
of amyloid fibrils. Different fibril types have different structures and
hence different fluorescence from the bound LCP
known which structures are most relevant for disease. A number of
LCPs displayed spectral discrimination of amyloid structures both
from the same protein‚ (PrP, Aß) as well as for discrimination of
different amyloids within the same patient (Aß, Tau). In addition,
we have shown that pre-fibrillar aggregates of PrP, and Aß
(oligomers) that are undetectable by conventional amyloid ligands
NEURODEGENERATIVE RESEARCH
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