Many neurodegenerative diseases are characterized by the conformational change of self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high ?-sheet content and resistance to degradation. Alzheimer's disease (AD) is the most common of the neurodegenerative protein conformational disorders, which include diffuse Lewy body disease (DLBD), Parkinson's disease (PD), prion diseases, and frontotemporal lobar degeneration (FTLD). The most toxic conformers are the oligomeric forms. None of the conformational diseases has an effective therapy;however, immunomodulation has shown great promise for both AD and prion diseases. Major problems with this approach include: the potential of toxicity from encephalitis (related to excessive cell mediated immunity), the immunological targeting of both the normal and abnormal A?, the resistance of vascular amyloid to clearance, as well as tau related pathology not being specifically addressed. The central hypothesis of this proposal is that each of these limitations can be overcome by specific targeting of abnormal oligomer conformation and development of novel methods to prevent oligomer mediated toxicity. Our novel active immunomodulation approach uses a polymerized British amyloidosis (pABri) related peptide in a predominantly ?-sheet, oligomeric form. We hypothesized that through """"""""conformational mimicry"""""""" the polymerized ABri peptide could induce a conformation selective immune response that will recognize both A? and conformationally abnormal tau. This hypothesis is supported by preliminary data in an APP/PS1 AD mouse model. Such an immunostimulatory approach should have a reduced risk of inducing auto-immune complications as it is more specific to a pathological conformer and the immunogen has no sequence homology to any known mammalian protein/peptide. We also present preliminary data that short term treatment with monoclonal 6D11, an anti-PrP antibody, reverses behavioral deficits in an AD model APP/PS1 Tg mice. This antibody blocks the binding of A? oligomers to PrPC. We hypothesize that blocking the binding of A? oligomers and PrPC is a novel therapeutic strategy for AD. These complementary approaches will aim to both increase clearance of A? oligomers and specifically block their toxicity.

Public Health Relevance

Many neurodegenerative diseases are characterized by the conformational change of self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high ?-sheet content and resistance to degradation. Alzheimer's disease (AD) is the most common of the neurodegenerative protein conformational disorders, which include diffuse Lewy body disease (DLBD), Parkinson's disease (PD), prion diseases, and frontotemporal lobar degeneration (FTLD). The most toxic conformers are the oligomeric forms, which we plan to target by developing novel approaches to both increase their clearance and to reduce their toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073502-02
Application #
8130878
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (02))
Program Officer
Corriveau, Roderick A
Project Start
2010-09-01
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$362,294
Indirect Cost
Name
New York University
Department
Neurology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Rubenstein, Richard; Chang, Binggong; Grinkina, Natalia et al. (2017) Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein. Acta Neuropathol Commun 5:30
Liu, Shan; Park, Shinae; Allington, Grant et al. (2017) Targeting Apolipoprotein E/Amyloid ? Binding by Peptoid CPO_A?17-21?P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline. Sci Rep 7:8009
Goñi, Fernando; Martá-Ariza, Mitchell; Peyser, Daniel et al. (2017) Production of Monoclonal Antibodies to Pathologic ?-sheet Oligomeric Conformers in Neurodegenerative Diseases. Sci Rep 7:9881
Drummond, Eleanor; Nayak, Shruti; Faustin, Arline et al. (2017) Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer's disease. Acta Neuropathol 133:933-954
Drummond, Eleanor; Wisniewski, Thomas (2017) Alzheimer's disease: experimental models and reality. Acta Neuropathol 133:155-175
Boutajangout, Allal; Noorwali, Abdulwahab; Atta, Hazem et al. (2017) Human Umbilical Cord Stem Cell Xenografts Improve Cognitive Decline and Reduce the Amyloid Burden in a Mouse Model of Alzheimer's Disease. Curr Alzheimer Res 14:104-111
Wegiel, Jerzy; Flory, Michael; Kuchna, Izabela et al. (2017) Multiregional Age-Associated Reduction of Brain Neuronal Reserve Without Association With Neurofibrillary Degeneration or ?-Amyloidosis. J Neuropathol Exp Neurol 76:439-457
Drummond, Eleanor; Wisniewski, Thomas (2017) The use of localized proteomics to identify the drivers of Alzheimer's disease pathogenesis. Neural Regen Res 12:912-913
Scholtzova, Henrieta; Do, Eileen; Dhakal, Shleshma et al. (2017) Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits. J Neurosci 37:936-959
Hickman, Richard A; Faustin, Arline; Wisniewski, Thomas (2016) Alzheimer Disease and Its Growing Epidemic: Risk Factors, Biomarkers, and the Urgent Need for Therapeutics. Neurol Clin 34:941-953

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