PROJECT SUMMARY/ABSTRACT – SUPPLEMENT Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, and the disease begins insidiously and silently 5-10 years before major symptoms appear such as progressive memory impairment, disordered cognitive function, altered behavior, and declined motor function. Neuropathological hallmarks of AD are neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and senile plaques comprising amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP). Thus, the agents that can effectively and safely reduce neurofibrillary tangles and Aβ oligomers during the early stages of AD provide promising therapeutic and potential prophylactic treatments in neurodegenerative diseases, including AD and/or its related dementias. Currently, there are numerous NPs reported in the literature aiming to target AD and other neurodegenerative diseases. However, every NP described in the literature to date suffers from two fundamental flaws: 1) long half-life that increases the accumulation of NP in the body and/or 2) nonspecific uptake in normal tissues, both of which significantly increase concerns about immunogenicity and toxicity. In our parent R01 project (R01 HL143020), we reported a new class of ultrasmall NP-based iron chelation therapies for systemic elimination of excessive iron and amelioration of iron-associated cardiovascular dysfunction. Our deferoxamine-coated nanochelators demonstrated a very high binding affinity to iron during circulation, followed by rapid, exclusive excretion into urine without nonspecific tissue uptake or accumulation in the body. Consequently, our nanochelators significantly decreased systemic and renal toxicities that were associated with the native iron chelator deferoxamine (Kang et al., Nature Communications 2019). Thus, our results suggest that the concept of “chelation”, if proper ligands (chelators) are conjugated to urine-specific ultrasmall NPs, could be applied to other disease conditions, by extension, in which pathogenic molecules are the cause of the disease, and therefore the removal of pathogenic molecules is essential for the effective treatment. Inspired by our recent accomplishment in nanochelation therapies, the hypothesis guiding this administrative supplement is that NPs that contain Aβ-specific ligands (Aβ-nanochelators) will capture fluidic, pathogenic Aβ peptides in the body even before forming prefibrillar Aβ or toxic oligomers in the brain, followed by rapid urinary excretion. Moreover, analysis of Aβ peptides concentrated in urine will increase sensitivity and quantification of subtle changes in systemic and total brain Aβ levels, which will significantly improve clinically relevant decision in AD diagnosis. Finally, elimination of circulating prefibrillar Aβ aggregates from the brain can tackle to the prevention and treatment of AD by reducing the potential deposition of Aβ plaques in the brain even at the very early stage. This admi...