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Beta Amyloid, Pir-B and Cofilin Involvement in Alzheimer's D

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Ndeye Fatou GUEYE

on 30 March 2014

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Transcript of Beta Amyloid, Pir-B and Cofilin Involvement in Alzheimer's D

Alzheimer's Disease
Beta Amyloid, Pir-B and Cofilin Involvement in Alzheimer's Disease
Hallmarks
Causes
Paired Immunoglobulin-like
Receptor B
Characterisation
Immunological Background
Proposed Role in Alzheimer's Disease
Grant Proposal
Role of Beta Amyloid
Specific Aims
I. Determining whether inhibition of PP2A and PP2B/calcineurin following binding of Beta Amyloid to PirB inactivates cofilin
APP/PS1 transgenic mice injected with PP2A and/or PP2B inhibitors and cofilin phosphorylation measured using IFC


II. Signalling mechanism: from binding of Beta Amyloid to PirB to activation of cofilin
Co-immunoprecipitation of hippocampal neurons to determine binding between Pir-B, PP2A or PP2B and cofilin
Mass spectrometry for
de novo
sequencing and protein structure determination if other proteins are found to be associated with Pir-B, PP2A or PP2B and cofilin



III. Potential Therapeutic Targets
APP/PS1 and PirB-/- mice studied to determine which steps of the pathway are the best potential targets for therapeutic intervention
Adapted from
Promiscuous Alzheimer's Amyloid: Yet Another Partner
, by Iryna Benilova and Bart De Strooper. Science 341, 1354 (2013)
Expected Outcomes
References
Some potential causes are:

Genetics
Mutations in APP and presinilin-1/2 genes

Amyloid hypothesis
Beta Amyloid deposition

Tau hypothesis
Tau hyperphosphorylation leads to neuronal death
Adapted from
Kuby Immunology: 7th Edition
(page 84)
Owen, Punt and Stranford
W. H. Freeman and Company (2013)
Amyloid plaques
Neurofibrillary tangles
Neuritic plaques
Atrophy and loss of neurons



Loss of memory
Impaired motor coordination
Speech difficulties
Behavioural changes
Death
Expressed on several haematopoietic cell lineages
B cells, mast cells, macrophages, granulocytes, dendritic cells
Not expressed on T and NK cells
Also expressed by neurons; present in neuronal growth cones and synapses

Homolog of human Leukocyte Immunoglobulin-like Receptor B2 (LILR-B2)

Binds non-classical MHC class I molecules for inhibitory signalling in immune response

Involved in
Recovery following a stroke (ischaemia)
Inhibition of axonal regeneration
Beta-Amyloid-mediated neurotoxicity
Neuronal plasticity
Type I transmembrane glycoprotein
Six EC Ig-like domains
Hydrophobic transmembrane domain
IC domain with 4 ITIMs
Immunoreceptor Tyrosine-based Inhibitory Motifs

Involved in down-regulation of immune responses
Beta Amyloid known to lead to activation of cofilin and of phosphatases PP2A and calcineurin (PP2B)
Cofilin associates with PirB both in vivo and in vitro
Signalling pathway is not well understood
Aim I
May observe different levels of cofilin phosphorylation when PP2A or PP2B is inhibited

Aim II
4 possibilities
Tripartite complex
No association of the three proteins by co-IP
Two of the proteins may associate
Association of proteins observed, but weight does not correspond to our proteins of interest
Questions?
Genome-wide association studies in Alzheimer's disease
, Waring, S.C and Rosenberg, R.N.
Archives of Neurology
, Volume 65, Issue 3, March 2008, pages 329-334

Paired immunoglobulin-like receptors and their MHC class I recognition
, Takai, T.
Immunology
, Volume 115, pages 433-440

Neuroprotection from Stroke in the Absence of MHCI or PirB
, Adelson et al.
Neuron
, 73, 22 March 2012, pages 1100-1107

PirB is a functional receptor for myelin inhibitors of axonal regeneration
, Atwal et al.
Science
, Volume 322, 7 November 2008, pages 967-970

Spatio-temporal expression of paired immunoglobulin-like receptor-B in the adult mouse brain after focal cerebral ischaemia
, Gou et al.
Brain Injury
, Volume 27, Issue 11, 2013, pages 1311-1315

Human LilrB2 is a Beta-Amyloid Receptor and its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer's Model
, Kim, T et al.
Science
, Volume 341, 20 September 2013, pages 1399-1404

Promiscuous Alzheimer's Amyloid: Yet Another Partner
, Benilova, I. and De Strooper, B.
Science
, Volume 341, 20 September 2013, pages 1354-1355

Amyloid-Beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks
, Palop, J.J and Mucke, L.
Nature Neuroscience
, Volume 13, Number 7, July 2010, pages 812-818


Alzheimer's Association (www.alz.org)
Kim et al. (2013)
PirB-IRES-EGFP–transfected (top) or control IRES-EGFP–transfected (bottom) HEK293 cells (green) were treated with mono- or oligo-Ab42 (100 nM total peptide, monomer equivalent), and bound Ab42 (red) was visualized. See also fig. S1. DAPI, 4´,6-diamidino-2-phenylindole
A) PirB interacts with cofilin in vivo in PirB+/− Tg mice (P30, forebrain), assessed by immunoprecipitation for PirB. Other known PirB-proximal signaling and interactions such as tyrosine phosphorylation of PirB and SHP-2 recruitment to PirB are not altered in PirB+/− relative to PirB+/− Tg mice. Representative data are shown (n > 2).

B) and C) Cofilin phosphorylation is reduced in both (B) juvenile (P30, forebrain) and (C) adult (P200, hippocampal synaptosomes) PirB+/−; APP/PS1 (PirB+/− Tg) mice relative to PirB+/− mice, and this reduction is rescued by PirB deletion (PirB−/− Tg). No significant alterations in LIM kinase (LIMK) 1/2 phosphorylation (Thr508/Thr505) were detected.
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