Keynote Conference - Interevent

L#17
Synapse failure induced by Alzheimer's toxic Aβ oligomers
Sérgio Teixeira Ferreira
Biomedical Sciences Institute, Federal University of Rio de
Janeiro (UFRJ), Rio de Janeiro, Brazil
More than one hundred years after its original description, the
mechanisms leading to memory loss and progressive cognitive
impairment in Alzheimer’s disease (AD) remain controversial.
Considerable evidence accumulated during the past decade
implicates soluble oligomers of the amyloid-β peptide (Aβ),
which accumulate in the brains of AD patients, as the proximal
toxins that attack neurons and cause synapse failure
culminating with memory impairment. This presentation will
focus on mechanisms by which Aβ oligomers (AβOs) attack
synapses and negatively impact the function of neuronal
receptors important for synaptic plasticity. We recently
showed that AβOs cause aberrant activation of NMDA
receptors, which triggers dysregulation of intracellular Ca2+
levels, neuronal oxidative stress and receptor internalization.
Similarly, AβOs induce removal of AMPA receptors from
synapses. Along with changes in pre-synaptic neurotransmitter
vesicle release, combined removal of NMDA and AMPA
receptors from synapses may be part of the mechanism by
which AβOs inhibit synaptic plasticity. We also demonstrated
that NMDA receptors play a key role in the binding of Aβ
oligomers to a neuronal receptor complex that putatively
comprises additional protein components, among which the
cellular prion protein. Finally, our recent work has shown that
A Os inhibit neuronal insulin signaling, essential for neuronal
survival, synaptic plasticity and memory formation. Elucidation
of molecular/cellular mechanisms underlying the deleterious
impact of AβOs on synapses may illuminate the development
of novel therapeutic approaches to combat memory loss in AD.
Key words: synaptotoxicity, amyloid- , memory loss
L#18
Collective cancer invasion, tissue guidance, and plasticity of
therapy response
Peter Friedl 1,2
1 Radboud University Nijmegen Medical Centre, Nijmegen, The
Netherlands and
2 The University of Texas, MD Anderson Cancer Center,
Houston, TX, USA
The tumor microenvironment contributes to cancer invasion,
growth and survival with impact on tumor response to therapy.
We here employ intravital infrared multiphoton imaging for the
multi-parameter visualization of cancer invasion, guidance by
the tumor stroma, and therapy response. The data show
predominantly collective cancer cell into the host stroma at
speeds of up to 200 µm per day. Invasion resulted from nondestructive
contact-guidance type migration exploiting
preformed tracks of multi-interface topography, including 1D,
2D and 3D dimensionalities, but was independent of β1 and β3
integrin-mediated mechanotransduction. Collective invasion
was coupled to altered survival capability, withstanding highdose
radiotherapy and forming a resistance niche for
subsequent relapse of the disease. Albeit invasion was integrinindependent,
invasion-associated radioresistance was sensitive
to the β1/β3 integrin targeting by RNAi or antiantibody
treatment, resulting in anoikis induction and regression
of both, tumor lesion and invasion strands. In conclusion,
collective invasion is an important invasion mode in solid tumors
that receive integrin signals from the tissue microenvironment
for acquiring an altered phenotype and improved survival.
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