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Beta Amyloid, Pir-B and Cofilin Involvement in Alzheimer's D
Transcript of Beta Amyloid, Pir-B and Cofilin Involvement in Alzheimer's D
Beta Amyloid, Pir-B and Cofilin Involvement in Alzheimer's Disease
Proposed Role in Alzheimer's Disease
Role of Beta Amyloid
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
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
Promiscuous Alzheimer's Amyloid: Yet Another Partner
, by Iryna Benilova and Bart De Strooper. Science 341, 1354 (2013)
Some potential causes are:
Mutations in APP and presinilin-1/2 genes
Beta Amyloid deposition
Tau hyperphosphorylation leads to neuronal death
Kuby Immunology: 7th Edition
Owen, Punt and Stranford
W. H. Freeman and Company (2013)
Atrophy and loss of neurons
Loss of memory
Impaired motor coordination
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
Recovery following a stroke (ischaemia)
Inhibition of axonal regeneration
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
May observe different levels of cofilin phosphorylation when PP2A or PP2B is inhibited
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
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.
, Volume 115, pages 433-440
Neuroprotection from Stroke in the Absence of MHCI or PirB
, Adelson et al.
, 73, 22 March 2012, pages 1100-1107
PirB is a functional receptor for myelin inhibitors of axonal regeneration
, Atwal et al.
, 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.
, 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.
, Volume 341, 20 September 2013, pages 1399-1404
Promiscuous Alzheimer's Amyloid: Yet Another Partner
, Benilova, I. and De Strooper, B.
, 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.
, 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.