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Principal Investigator: Amer Alam
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2021
Award: $435,750
Funding agency: National Institute on Aging
Project Summary
Alzheimer’s disease (AD) represents one of the foremost healthcare challenges of our times and is a leading
cause of death worldwide. AD accounts for the overwhelming majority of dementias, which affect over 35 million
people worldwide. This number is expected to double every twenty years. Dysfunction of the Adenosine
triphosphate (ATP) Binding Cassette Subfamily A member 7 (ABCA7) transporter has been linked to both early
and late onset AD through alterations in lipid homeostasis, Amyloid-Beta (Aβ) homeostasis, and phagocytosis.
ABCA7 single nucleotide polymorphisms have been associated with late onset AD, suggesting that targeting
ABCA7 could pave the way forward for new therapeutic AD strategies. The long-term objectives of this project
are to gain mechanistic insight into human ABCA7 (hABCA7). We will use a combination of high-resolution
structural analysis, in vitro functional characterization, and discovery of antibody and small molecule binders for
hABCA7. The latter will aid in diagnostics and targeting, or function as potentiators and/or correctors of hABCA7
dysfunction. Specific Aim 1 deals the functional characterization of ABCA7 ATPase activity and the
establishment of an in vitro transport assay to assay the lipid specificities and transport properties of the
transporter and probe its interaction with different apolipoproteins. Specific Aim 2 deals with the detailed cryo-
EM analysis of hABCA7 alone and in combination with nucleotides, different lipid environments, and small
molecule and antibody based binders. Our results will shed light on the physiological functioning of human
ABCA7, which is as of yet poorly understood, and validate its potential utilization as a therapeutic target for which
future antibody and drug discovery efforts can be directed, thereby bridging basic and translational research for
this relatively unexplored area of AD research.
Terms: <ABC Transport Protein><ABC Transporter Protein><ABC Transporters><ABCA1><ABCA1 protein><AD dementia><ATP binding cassette transporter 1><ATP phosphohydrolase><ATP-Binding Cassette Transporters><ATPase><Accounting><Adenosine Triphosphatase><Adenosine Triphosphate><Adenosinetriphosphatase><Adenylpyrophosphate><Affect><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><Alzheimer's disease dementia><Alzheimer's disease therapeutic><Alzheimer's disease therapy><Alzheimer's therapeutic><Alzheimer's therapy><Alzheimers Dementia><Alzheimers disease><Amentia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Animals><Antibodies><Apo A-1><Apo A-I><Apo A1><Apo AI><Apo-A><Apo-E><ApoA><ApoA-1><ApoA-I><ApoE><Apolipoprotein A-1><Apolipoprotein A-I><Apolipoprotein A1><Apolipoprotein AI><Apolipoprotein E><Apolipoproteins><Apolipoproteins A><Area><Assay><Autoregulation><Aβ><Basic Research><Basic Science><Binding><Bioassay><Biochemical><Biologic Assays><Biological><Biological Assay><Biological Markers><Cause of Death><Cell Body><Cells><Cessation of life><Characteristics><Cholesterol><Choline Glycerophospholipids><Choline Phosphoglycerides><Collaborations><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Custom><Data><Death><Dementia><Development><Diagnostic><Disease Progression><Dysfunction><Electron Cryomicroscopy><Environment><Foundations><Functional disorder><Future><GWA study><GWAS><Genetic Polymorphism><HDLDT1><Healthcare><Homeostasis><Human><Hydrolysis><Immobilization><In Vitro><Isoforms><Knock-out><Knockout><Late Onset Alzheimer Disease><Lecithin><Libraries><Light><Link><Lipid Bilayers><Lipids><Lipoproteins><Liposomal><Liposomes><Maintenance><Membrane><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Nucleotides><Onset of illness><Pathogenesis><Pathway interactions><Phagocytosis><Phosphatidylcholines><Photoradiation><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Primary Senile Degenerative Dementia><Process><Production><Property><Protein Isoforms><Research><Resolution><Saposins><Scaffolding Protein><Single Base Polymorphism><Single Nucleotide Polymorphism><Specificity><Spin Labels><Structure><Testibumin><Therapeutic><Time><Translational Research><Translational Science><Up-Regulation><Upregulation><Wild Type Mouse><Work><a beta peptide><abeta><age dependent><age related><amyloid beta><amyloid-b protein><base><beta amyloid fibril><bio-markers><biologic marker><biomarker><cholesterol-efflux regulatory protein><clinical applicability><clinical application><combat><conformation><conformational state><cryo-EM><cryoEM><dementia of the Alzheimer type><developmental><disease onset><disorder onset><drug discovery><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><health care><insight><late onset alzheimer><lipid bilayer membrane><member><membrane structure><metabolism measurement><metabolomics><metabonomics><mutant><nano disk><nano particle><nano-sized particle><nanobodies><nanobody><nanodisk><nanoparticle><nanosized particle><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><orthopedic freezing><pathophysiology><pathway><polymorphism><primary degenerative dementia><reconstitute><reconstitution><screening><sdAb><senile dementia of the Alzheimer type><single domain antibodies><single nucleotide variant><small molecule><soluble amyloid precursor protein><therapeutic target><translation research><whole genome association analysis><whole genome association studies><whole genome association study><wildtype mouse>