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Principal Investigator: Olga Gursky
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $106,758
Funding agency: National Institute of General Medical Sciences
Abstract
Amyloid diseases afflict >10 million patients worldwide and involve pathologic deposition of ~40 human proteins
as fibrils. This project is focused on AA amyloidosis, a life-threatening complication of chronic inflammation
wherein deposition of a small plasma protein, serum amyloid A (SAA), and its fragments causes kidney and liver
damage and, if untreated, death. There is no cure for AA and the treatment options are very limited. To help
design amyloid-specific therapies, we will determine how lipids and glycosaminoglycans (GAGs), the major lig-
ands of SAA, influence its misfolding. Our prior research revealed that SAA clears diverse lipids from the sites
of injury by sequestering them into nanoparticles that facilitate sPLA2 lipolysis; we established the structural basis
for this SAA action. Our goal now is to determine how this lipid-scavenging function is linked to pathologic amyloid
deposition. Our hypothesis rooted in extensive pilot studies is that lipoprotein formation by SAA is antagonistic to
amyloid formation while GAG binding is agonistic. Our powerful approach integrates a wide array of biochemical,
biophysical and computational methods to test this and other new ideas in three complementary Specific Aims.
Aim 1 will determine how biochemical composition of SAA-lipid complexes influences amyloid formation. Murine
or human recombinant SAA will be reconstituted with diverse lipids in complexes that will be selectively hydro-
lyzed, and amyloid formation will be explored by spectroscopic, electron microscopic, immunochemical and other
tools. The results will help identify key steps in SAA-lipid homeostasis that critically influence amyloid formation,
and will test a fascinating idea: lipid-modifying strategies may help treat AA amyloidosis. Aim 2 will dissect the
amyloidogenic pathway of lipid-bound and free SAA and the effects of GAGs. Our multipronged experimental-
computational approach will explore the interplay between SAA binding to lipids, to GAGs, and formation of
amyloid oligomers and fibrils. SAA-GAG interactions are a validated therapeutic target in AA, but a small-mole-
cule drug designed to block them was inefficient in clinical trials. Our hypothesis is that GAGs act as amyloid
scaffolds; to test it, we will harness cryo-EM structures of ex vivo amyloids for molecular dynamics simulations.
The results will help target SAA-GAG interactions in AA and will provide sharp insights into amyloid-GAG inter-
actions in other diseases. Aim 3 will utilize our new versatile ELISA-based assay that uses micrograms of protein
to quantify the binding to amyloid modulators during fibrillogenesis. SAA binding to various GAG mimetics and
small-molecule drugs will be used as a model; key results will be validated by other methods. Our pilot studies
explain the failure of prior clinical trials for AA and suggest that larger molecules can block the SAA-GAG binding.
Moreover, we will use our new assay to determine how other amyloid proteins (Aβ, α-synuclein, tau, TTR, etc.)
interact with diverse amyloid modulators (GAGs, apoE, etc.) Impact: this project will advance AA research and
therapeutic targeting to a new level. Moreover, it will develop new tools and concepts that can be extrapolated
to other systemic and neurodegenerative amyloid diseases, such as Alzheimer's and other major diseases.
Terms: <AD dementia><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimers Dementia><Amyloid><Amyloid A Precursor><Amyloid A Protein-Related Serum Component><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Protein AA Precursor><Amyloid Protein SAA><Amyloid Proteins><Amyloid Serum Protein SAA><Amyloid Substance><Amyloid beta-Protein><Amyloid deposition><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Amyloid-Related Serum Protein (SAA)><Amyloidosis><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Assay><Autoregulation><Aβ><Binding><Bioassay><Biochemical><Biological Assay><Cessation of life><Chronic><Clinical Trials><Complex><Complication><Computing Methodologies><Cryo-electron Microscopy><Cryoelectron Microscopy><Death><Deposit><Deposition><Disease><Disorder><Drug Design><Drugs><ELISA><Electron Cryomicroscopy><Electrons><Enzyme-Linked Immunosorbent Assay><Failure><Glycosaminoglycans><Goals><Health><Homeostasis><Human><Inflammation><Injury><Injury to Liver><Life><Ligands><Link><Lipid Binding><Lipids><Lipolysis><Lipoproteins><MT-bound tau><Medication><Methods><Mice><Mice Mammals><Microscopic><Modeling><Modern Man><Molecular Dynamics Simulation><Molecular Interaction><Mucopolysaccharides><Murine><Mus><NAC precursor><Negative Beta Particle><Negatrons><Nerve Degeneration><Neuron Degeneration><Organ><PARK1 protein><PARK4 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathway interactions><Patients><Pharmaceutical Preparations><Physiological Homeostasis><Pilot Projects><Plasma Proteins><Play><Primary Parkinsonism><Primary Senile Degenerative Dementia><Proteins><Public Health><Recombinants><Research><Role><SNCA><SNCA protein><Serum A Related Protein><Serum Amyloid A><Serum amyloid A protein><Site><Structure><Testing><a beta peptide><a-syn><a-synuclein><abeta><alpha synuclein><alpha synuclein gene><alphaSP22><amyloid assembly><amyloid beta><amyloid disease><amyloid formation><amyloid-b protein><asyn><beta amyloid fibril><biophysical approaches><biophysical methodology><biophysical methods><biophysical techniques><computational methodology><computational methods><computer based method><computer methods><computing method><cryo-EM><cryoEM><cryogenic electron microscopy><damage to kidney><design><designing><drug/agent><enzyme linked immunoassay><fascinate><fibrillogenesis><hepatic damage><hepatic injury><injured><injuries><insight><insoluble aggregate><kidney damage><lipid bound><liver damage><liver injury><microtubule bound tau><microtubule-bound tau><mimetics><molecular dynamics><nano particle><nano-sized particle><nanoparticle><nanosized particle><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><non A-beta component of AD amyloid><non A4 component of amyloid precursor><pathway><pilot study><primary degenerative dementia><protein aggregate><protein aggregation><reconstitute><reconstitution><renal damage><scaffold><scaffolding><senile dementia of the Alzheimer type><small molecule><social role><soluble amyloid precursor protein><tau><tau Proteins><tau factor><therapeutic target><tool><α synuclein gene><α-syn><α-synuclein><τ Proteins>