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Principal Investigator: Joel Kaar
Organization: UNIVERSITY OF COLORADO
Fiscal Year: 2019
Award: $198,980
Funding agency: National Institute on Aging
SUMMARY
The formation of amyloid fibrils due to protein aggregation represents a central step in the pathogenesis of many
age-related diseases for which there are no current cures. At the core of this step is the misfolding of one or
more key proteins, which is converted from a natively folded or unfolded state to an aggregation-prone state that
is rich in b-sheet structure. While there have been intensive efforts to develop therapeutic approaches to inhibit
amyloid fiber formation during its initial stages, such strategies have met with only limited success. As such,
there remains a need for alternative strategies to mediate even earlier states of amyloid oligomerization by re-
folding and thus rescuing misfolded proteins prior to aggregating. The overall aim of this proposal is to develop
nanomaterials with chaperone-like activity to promote re-folding of misfolded proteins and thus have therapeutic
potential to inhibit amyloid formation. Specifically, in this approach, we propose to rationally modify nanoparticles
with novel coatings that stabilize the native structure of amyloid-associated proteins and can be delivered in vivo.
Of particular interest will be investigating the extent to which chemically heterogeneous polymer brushes and
mixed lipid bilayers promote re-folding of the protein amyloid-b (Ab42), which is a precursor to amyloid fibers
that are formed in Alzheimer’s disease. In support of this approach, we have previously shown that random co-
polymer brushes composed of poly(ethylene glycol) and poly(sulfobetaine) as well as mixed supported lipid
bilayers compared of varying ratios of 1,2-dioleoyl-sn-glycero-3-phosphocholine and 1,2-dioleoyl-sn-glycero-3-
phospho-(1'-rac-glycerol) both stabilized and promoted the re-folding of model proteins, including fibronectin and
nitroreductase. Using coatings made of such materials, we will test the central hypothesis that nanoparticles
coated with dynamic and heterogeneous layers can reduce the conversion of Ab42 to its aggregation-prone state
and prevent amyloid formation via a chaperone-like mechanism. In line with this hypothesis, the specific aims of
this proposal are to: (1) elucidate the mechanism and optimize the composition of heterogeneous coatings for
Ab42 stabilization by nanoparticles via a chaperone-like mechanism (Aim 1) and (2) correlate Ab42 stabilization
by chemically heterogeneous nanoparticles with the inhibition amyloid formation (Aim 2). The chaperone-like
activity of the nanoparticle coatings will be characterized quantitatively using single-molecule biophysical
methods that are uniquely sensitive to monitoring protein structure and dynamics (e.g., re-folding) on surfaces.
To correlate the stabilization of Ab42 with the inhibition of amyloid formation, the impact of the coatings on the
formation of amyloid fibrils will be measured in the presence of coated and uncoated nanoparticles while varying
coating composition. Additionally, the utility of the coated nanoparticles in inhibiting the aggregation of Ab42 and
Ab40 as well as Ab42 with mutations associated with Alzheimer’s disease (i.e., E22G) will also be measured.
These studies will provide a complete molecular picture of this approach, as well as a general understanding
that may be applied to the rescue of proteins implicated in other protein misfolding diseases, including cancer.
Terms: <1,2,3-Propanetriol><1,2,3-Trihydroxypropane><1,2-Ethanediol><2-Hydroxyethanol><Address><Aging><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimers Dementia><Alzheimers disease><Amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid fibers><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Assay><Aβ><Beta Sheet><Binding><Bioassay><Biologic Assays><Biological Assay><CJD><Cancers><Chaperone><Chemicals><Choline Chloride Dihydrogen Phosphate><Choline Phosphate><Choline Phosphate Chloride><Circular Dichroism><Cold-Insoluble Globulins><Creutzfeldt-Jacob Disease><Creutzfeldt-Jakob Disease><Creutzfeldt-Jakob Syndrome><Cristobalite><Dihydroxyethanes><Disease><Disorder><EOAD><Early Onset Alzheimer Disease><Ethanediols><Ethylene Glycols><FN1><FRET><Fiber><Fibronectin 1><Fibronectins><Fluorescence><Fluorescence Resonance Energy Transfer><Future><Förster Resonance Energy Transfer><Genetic Alteration><Genetic Change><Genetic defect><Glycerin><Glycerol><Jakob-Creutzfeldt Disease><Kinetics><LETS Proteins><Large External Transformation-Sensitive Protein><Lead><Link><Lipid Bilayers><Literature><Malignant Neoplasms><Malignant Tumor><Measurement><Measures><Mediating><Methods><Modeling><Molecular><Molecular Chaperones><Molecular Interaction><Monitor><Monoethylene Glycol><Mutation><Nitroreductases><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Paralysis Agitans><Parkinson><Parkinson Disease><Parkinson's><Parkinson's disease><Parkinsons disease><Pathogenesis><Patients><Pb element><Peptides><Phosphocholine><Phosphorylcholine><Phosphorylcholine Chloride><Polymers><Presenile Alzheimer Dementia><Primary Parkinsonism><Primary Senile Degenerative Dementia><Protein Dynamics><Proteins><Sand><Silica><Silicon Dioxide><Structural Protein><Structure><Subacute Spongiform Encephalopathy><Surface><Testing><Therapeutic><Tridymite><Work><a beta peptide><aberrant protein folding><abeta><abnormal protein folding><age dependent><age related><alpha 2-Surface Binding Glycoprotein><amyloid assembly><amyloid beta><amyloid fibril formation><amyloid formation><amyloid structure><amyloid-b protein><antibody engineering><beta amyloid fibril><beta pleated sheet><biophysical approaches><biophysical methodology><biophysical methods><biophysical techniques><dementia of the Alzheimer type><early onset AD><ethylene glycol><familial AD><genome mutation><heavy metal Pb><heavy metal lead><in vivo><innovate><innovation><innovative><insight><interest><lipid bilayer membrane><malignancy><misfolded protein><mutant><nano materials><nano particle><nano-sized particle><nanomaterials><nanoparticle><nanosized particle><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapy approach><pathologic protein folding><pre-clinical study><preclinical study><prevent><preventing><primary degenerative dementia><protein aggregation><protein folding><protein mis-folding><protein misfolding><protein structure><proteotoxic protein><proteotoxin><senile dementia of the Alzheimer type><single molecule><small molecule><soluble amyloid precursor protein><success><β-Sheet><β-pleated sheet>