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Volume 9
Journal of Neurology and Neuroscience
ISSN: 2171-6625
Page 46
JOINT EVENT
July 23-24, 2018 Birmingham, UK
&
24
th
International Conference on
Neuroscience and Neurochemistry
26
th
Edition of International Conference on
Clinical Psychology and Neuroscience
Drug discovery for Alzheimer’s disease: A focus on small molecule able to disrupt PrPC - Aβos
binding, to block PrPC-dependent cognitive defects
Imane Ghafir El Idrissi
1, 2, 3
, Nicola Antonio Colabufo
1, 2
and
Beining Chen
3
1
Biofordrug srl, Italy
2
Università degli Studi di Bari Aldo Moro, Italy
3
University of Sheffield, UK
A
lzheimer’s disease (AD) is characterized by a severe loss of memory function. It has been proposed that AD associated
memory loss is caused by soluble amyloid-beta oligomers (OS), especially during early stages of AD before significant
neuronal cell death has occurred. It has been shown that PrPC mediates the toxic effect of Aβ oligomers and is required for Aβ
oligomer-induced suppression of synaptic plasticity, synapse damage, and neuronal cell death Aβos binding to PrPC results
in Fyn activation which leads to NR2B subunit of NMDARs phosphorylation and in tau hyperphosphorylation, the second
pathological hallmarks of AD. Treatment with PrPC antibodies against the Aβ oligomer binding site prevents the inhibition
of long-term potentiation and reverses cognitive deficits in AD transgenic mice. Copper ion (Cu
2+
) is another important
plyer in this scenario. In fact, the PrPC in its copper-loaded state binds to the NMDAR complex to allosterically reduce its
glycine affinity, thereby increasing desensitization. When copper is chelated (i.e., by BCS or monomeric Aβ1–42) or when
PrPC is absent or functionally compromised (by GPI anchor cleavage or binding to Aβ oligomers), glycine affinity is enhanced,
reducing receptor desensitization and producing pathologically large, steady-state currents that contribute to neuronal damage.
There has been considerable interest in identification of compounds that bind to PrPC, stabilizing its native fold and thereby
acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrPC could
also inhibit the binding of toxic species and may have a role in treating AD. The work outlined here details investigations
into a group of around 100 compounds. These were screened in HEK 293 and N2a differentiate cells, wild type expressing
PrPC in order to establish and optimize their
in vitro
ability to disrupt Aβ1-42-PrPC binding, establish their structure-activity
relationship and identify a lead compound.
Recent Publications
1. Chen RJ, et al. (2013) Alzheimer’s Amyloid β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the
Fyn Pathway. ACS Chem Neurosci. 18;4(9):1287-96.
2. LM Smith, et al. (2017) Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity. Cold Spring Harb Perspect Med.
Cold Spring Harb Perspect Med. 7(5).
3. M Larson, et al. (2012) The Complex PrPC-Fyn Couples Human Oligomeric Aβ with Pathological Tau Changes in
Alzheimer’s Disease. The Journal of Neuroscience 32:16857–16871.
4. Chung E et al. (2010) Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an
Alzheimer's disease model mouse. BMC Neurosci. 14(11):130.
5. You H, et al. (2012) Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-
aspartate receptors. Proc Natl Acad Sci USA 109(5):1737-42.
Biography
Imane Ghafir El Idrissi is a third year PhD student in Pharmaceutical and Medical Biomolecular Sciences at the University of Bari, Italy. Her thesis is entitled as
“Role of Prion protein and Involvement of metal ions in the onset of Alzheimer’s disease”. On 5th February 2018, she has been awarded with a scholarship in the
call for PhD mobility for study/research at University of Sheffield (UK) within the framework of the GLOBAL-DOC project. From October 2014 to September 2018,
she is involved in a Marie Skłodowska-Curie Action: Industry Academia Partnerships and Pathways (IAPP) Grant Agreement 612347 title D3i4AD and she spent
one year in Sheffield (UK), from October 2015 to March 2016 and from November 2016 to June 2017, during which she developed a cell-based assay, by using
HEK 293 cells, useful for a high-throughput screening of small molecules able to disrupt the binding of Aβ1-42 to PrPC, under the supervision of Prof Beining Chen
and Prof Nicola Antonio Colabufo.
ghafir.imane@gmail.comImane Ghafir El Idrissi et al., J Neurol Neurosci 2018, Volume 9
DOI: 10.21767/2171-6625-C2-012