Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy

Ambi, Ashwin; Stanisavljevic, Aleksandra; Victor-Lovelace, Tiffany W.; Lowery, Adam W.; Davis, Judianne; Van Nostrand, William E.; Miller, Lisa M.

doi:10.1021/acschemneuro.2c00483

Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy

Journal Article · Wed Jan 18 00:00:00 EST 2023 · ACS Chemical Neuroscience

DOI:https://doi.org/10.1021/acschemneuro.2c00483· OSTI ID:1973499

Ambi, Ashwin ^[1]; Stanisavljevic, Aleksandra ^[2]; Victor-Lovelace, Tiffany W. ^[3]; ^[4]; Davis, Judianne ^[2]; Van Nostrand, William E. ^[2]; ^[1]

Stony Brook Univ., NY (United States); Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)
Univ. of Rhode Island, Kingston, RI (United States)
Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)
Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II); Virginia Polytechnic Inst. and State Univ. (Virginia Tech), Blacksburg, VA (United States)

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer’s disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM), via intraperitoneal (IP) administration for 6 months to determine if it could lower copper content in vascular amyloid deposits and modify CAA pathology. In this work, results showed that TTM treatment led to elevated Aβ load in the hippocampus of the rTg-DI rats and increased microbleeds in the wild type (WT) animals. X-ray fluorescence microscopy was performed to image the distribution of copper and revealed a surprising increase in copper colocalized with Aβ aggregates in TTM-treated rTg-DI rats. Unexpectedly, we also found an increase in the copper content in unaffected vessels of both rTg-DI and WT animals. These results show that IP administration of TTM was ineffective in removing copper from vascular Aβ aggregates in vivo and increased the development of disease pathology in CAA.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 1973499

Report Number(s):: BNL-224373-2023-JAAM

Journal Information:: ACS Chemical Neuroscience, Journal Name: ACS Chemical Neuroscience Journal Issue: 3 Vol. 14; ISSN 1948-7193

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy

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