Chronic Heavy Alcohol Intake and Liver-specific LRP-1 Reduction Increase Amyloidosis in Alzheimer’s Disease Mice

Authors

Devaraj V. Chandrashekar, Chapman University
G. Chuli Roules, Chapman University
Ross A. Steinberg, Keck Graduate Institute
Urvashi R. Panchal, Chapman UniversityFollow
Nataraj Jagadeesan, Chapman University
Adenike Oyegbesan, Chapman University
Trinh Roselyn, Chapman University
Joshua Yang, Chapman University
Sharda R. Bhagwat, The Millennium School, India
Hiya Rakholia, The Millennium School, India
Rutvi D. Mevawala, The Millennium School, India
Moom Roosan, Chapman UniversityFollow
Derick Han, Keck Graduate Institute
Rachita K. Sumbria, Chapman UniversityFollow

Document Type

Article

Publication Date

1-3-2025

Abstract

Background

Chronic heavy alcohol drinking may be a modifiable risk factor for Alzheimer’s disease (AD), but studies in rodent AD models more closely mimic chronic moderate alcohol drinking in humans and largely focus on the brain. The role of the liver, which is significantly impacted by chronic heavy alcohol intake, in driving brain changes in alcohol-dependent AD remains unexplored. Our study using intragastric-ethanol feeding, which mimics chronic heavy alcohol intake in humans, in C57BL/6J mice showed significant AD-relevant changes in the brain and liver. Therefore, we aimed to investigate how hepatic changes using this model of chronic heavy drinking drive AD pathology in AD mice, which has never been attempted.

Methods

Eight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7-11/group). Brain and liver Aβ were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aβ regulator), blood-brain barrier (BBB) function (vascular Aβ regulator), and microglia (major brain Aβ regulator) using immunoassays. Hepatic LRP-1 expression was confirmed using Nanostring spatial transcriptomics. To elucidate the role of hepatic LRP-1 in brain amyloidosis, hepatic LRP-1 was silenced by injecting LRP-1 microRNA delivered by the adeno-associated virus 8 (AAV8) and the hepato-specific thyroxine-binding globulin promoter to 4-month-old male APP/PS1 mice (n = 6). Control APP/PS1 mice received control AAV8 (n = 6). Spatial memory was assessed 12 weeks after LRP-1 silencing using Y-maze, and brains and livers were harvested to detect Aβ.

Results

Alcohol feeding increased aggregated Aβ (p<0.05) by ELISA and 6E10-positive Aβ load (p<0.05) by immunostaining, and reduced plaque-associated microglia in APP/PS1 mice brains. Further, alcohol-fed APP/PS1 had liver steatosis and significantly downregulated hepatic LRP-1 (p<0.01) at the protein and transcript level, and brain and hepatic Aβ were positively correlated (p<0.05). Hepato-specific LRP-1 silencing significantly increased brain Aβ load (p<0.05) and reduced entries into the novel arm of the Y-maze (p<0.05) in APP/PS1 mice.

Conclusion

Chronic heavy alcohol intake reduced hepatic LRP-1 expression, and hepato-specific LRP-1 silencing increased brain Aβ and spatial memory deficits in APP/PS1 mice. Our results place hepatic LRP-1 as a potential key driver of brain amyloidosis in alcohol-dependent AD.

Comments

This article was originally published in Alzheimer's & Dementia, volume 20, issue S1, in 2024. https://doi.org/10.1002/alz.087662

Recommended Citation

Chandrashekar, D.V., Roules, G.C., Steinberg, R.A., Panchal, U.R., Jagadeesan, N., Oyegbesan, A., Roselyn, T., Yang, J., Bhagwat, S.R., Rakholia, H., Mevawala, R.D., Roosan, M., Han, D. and Sumbria, R.K. (2024), Chronic heavy alcohol intake and liver-specific LRP-1 reduction increase amyloidosis in Alzheimer’s disease mice. Alzheimer's Dement., 20: e087662. https://doi.org/10.1002/alz.087662

Copyright

The Alzheimer’s Association

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.