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(Postal-) Address:
Saarland
University
Neurodegeneration
and Neurobiologie
Neurology
Building
90
Kirrberger
Straße
66421
- Homburg / Saar
Germany
Phone:
+49 6841 - 1647918
Fax:
+49 6841 - 1624137
Email:
Tobias.Hartmann@Uniklinikum-Saarland.de
Lab members may be reached under the phone numbers +49
6841 - 16479- 16/17/19/20/21
Recent Research: Physiological function of
Amyloid-beta peptide (the peptide which causes Alzheimer's
disease) resolved.
In a fascinating hunt to identify
the biological function of Amyloid-beta, this question
has finally been resolved.  Amyloid-beta peptides are 40
and 42 amino acid long peptides (Aβ40 and Aβ42)
which accumulate in the brain where especially Aβ42
forms the infamous Amyloid plaques. This had been
discovered 20 years ago, but the physiological (that
is the non disease causin) function, these
peptides might have, remained enigmatic.
Shortly after the peptides had been identified, the
precursor protein (Amyloid Precursor Protein,
APP) could be identified as well. Although
an item of intense research and debate, the discovery
of the precursor protein did not result in the identification
of either APP or Amyloid-beta function.
Our research now shows, that Amyloid-beta,
while toxic and disease causing if over produced,
has a normal and non-toxic function, that is to regulate
cellular lipid levels. Their function results in regulatory
cycles in which the Amyloid-beta reduces cholesterol
synthesis (by lowering HMGR activity, the key
regulated enzyme in cholesterol de novo synthesis)
and sphingomyelin levels (by activating SMase,
a sphingomyelin degrading enzyme). Moreover,
the very same lipids control the activity of the
enzyme which produces Amyloid-beta, resulting in altered
Amyloid-beta peptide levels. Interference with these
regulatory cycles by pharmacological, genetic, or
even dietary means, changes Amyloid-beta production
and thus the risk for Alzheimer's disease.
Knowledge of the natural Amyloid-beta
peptide function allows us to re-evaluate therapeutic
and preventive approaches to Alzheimer's disease and
to generate more effective and safer novel therapies.
Moreover, it functionally explains the link between
Alzheimer's disease and cholesterol, and how statins
(cholesterol lowering drugs) work to prevent Alzheimer's
disease.
Download
the paper here, or at the publishers website (published at Nature Cell Biology,
9.th october 2005, advanced online publication).
Or read the university press release
or NGFN press release (both in german).
.
Introduction to the laboratory:
Neurobiology of diseases is one of the
most challenging and fascinating topics to study.
Neurodegenerative diseases are often very complex
and few treatments exist. We focus on Alzheimer's
disease, the major cause of dementia in industrialized
countries. Alzheimer's disease is always fatal and
even if the disease process could be stopped irreparable
damage has been done to the brain. Alois Alzheimer
described this disease already 1906 and ever since
it has been a focus of intense research. However,
progress was initially very slow and only in the very
last years curative treatments and preventions are
reaching the first stages of clinical trials. Our
research addresses the question of treating Alzheimer's
disease in three ways:
Prevention is always the most beneficial goal. To
prevent further disease progression and, whenever
possible, to achieve some degree of recovery in cognitive
capabilities are two important areas of research.
E.g. our lipid related research, with diet for prevention
and pharmaceuticals for treatment of disease progression,
addresses these questions. This research has progressed
to the first clinical stage and based on these results
patient studies are currently performed.
How do we develop such therapies? The core of our
research work is based on the understanding of the
molecular and cellular basis of Alzheimer's disease.
The molecular machinery and the cellular compartments
involved in this has been identified in great detail,
making Alzheimer's disease one of the most widely
studied diseases. However, our current knowledge is
that of a static system. Moreover, the normal biological
function of the majority of proteins involved in Alzheimer's
disease is not known. It is now important to understand
the biological role of these proteins and to identify
the factors that regulate this functional network
of proteins and other molecules. Only with a solid
understanding of the biological basis of the disease,
acceptable and effective treatments can be designed.
Selected Publications
Basic science research
Fassbender et al. The
LPS receptor (CD14) links innate immunity with Alzheimer's
disease (2004) Faseb J
Grimm H. et al. gamma-Secretase cleavage site specificity
differs for intracellular and secretory amyloid beta
(2003) J Biol Chem
Grziwa et al. The Transmembrane Domain of the Amyloid
Precursor Protein in Microsomal Membranes Is on Both
Sides Shorter than Predicted (2003) J Biol Chem
Runz et al. Inhibition of intracellular cholesterol
transport alters presenilin localization and amyloid
precursor protein processing in neuronal cells (2002)
J Neurosci
Fassbender et al. Simvastatin strongly reduces levels
of Alzheimer's disease betaamyloid peptides Abeta
42 and Abeta 40 in vitro and in vivo (2001) Proc Natl
Acad Sci U S A
Clinical oriented science
Simons et al. Treatment with simvastatin in normocholesterolemic
patients with Alzheimer's disease: A 26-week randomized,
placebo-controlled, double-blind trial (2002) Ann
Neurol
Reviews
Hartmann Cholesterol, Abeta and Alzheimer's disease
(Review) (2001) TINS
Textbook articles
Hartmann et al. (2003) in Lehrbuch der Gerontopsychatrie
und -psychotherapie (Förstel, H., ed), 2 Ed.,
pp. 273-279, Thieme, Stuttgart, New York
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