Hepatic LRP-1 Plays an Important Role in Amyloidosis in Alzheimer's Disease Mice: Potential Role in Chronic Heavy Alcohol Feeding

Authors

Devaraj V. Chandrashekar, Chapman University
G. Chuli Roules, Chapman University
Nataraj Jagadeesan, Chapman University
Urvashi R. Panchal, Chapman UniversityFollow
Adenike Oyegbesan, Chapman University
Oghenetega E. Imiruaye, Keck Graduate Institute
Hai Zhang, University of California, Irvine
Jerome Garcia, University of La Verne
Kamaljit Kaur, Chapman UniversityFollow
Sanda Win, University of Southern California
Tin A. Than, University of Southern California
Neil Kaplowitz, University of Southern California
Moom R. Roosan, Chapman UniversityFollow
Derick Han, Keck Graduate InstituteFollow
Rachita K. Sumbria, Chapman UniversityFollow

Document Type

Article

Publication Date

6-15-2024

Abstract

Background

Hepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aβ) clearance, but its importance in Alzheimer's disease (AD) pathology is understudied. Our previous work showed that intragastric alcohol feeding to C57BL/6 J mice reduced hepatic LRP-1 expression which correlated with significant AD-relevant brain changes. Herein, we examined the role of hepatic LRP-1 in AD pathogenesis in APP/PS1 AD mice using two approaches to modulate hepatic LRP-1, intragastric alcohol feeding to model chronic heavy drinking shown by us to reduce hepatic LRP-1, and hepato-specific LRP-1 silencing.

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. Spatial LRP-1 gene expression in the periportal versus pericentral hepatic regions was confirmed using NanoString GeoMx Digital Spatial Profiler. Further, 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 (TBG) promoter to 4-month-old male APP/PS1 mice (n = 6). Control male APP/PS1 mice received control AAV8 (n = 6). Spatial memory and locomotion were assessed 12 weeks after LRP-1 silencing using Y-maze and open-field test, respectively, and brain and liver Aβ were measured.

Results

Alcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aβ (p < 0.05) by ELISA and 6E10-positive Aβ load by immunostaining (p < 0.05). Increased brain Aβ corresponded with a significant downregulation of hepatic LRP-1 (p < 0.01) at the protein and transcript level, primarily in pericentral hepatocytes (zone 3) where alcohol-induced injury occurs. Hepato-specific LRP-1 silencing significantly increased brain Aβ and locomotion hyperactivity (p < 0.05) in APP/PS1 mice.

Conclusion

Chronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aβ. The hepato-specific LRP-1 silencing similarly increased brain Aβ which was associated with behavioral deficits in APP/PS1 mice. Collectively, our results suggest that hepatic LRP-1 is a key regulator of brain amyloidosis in alcohol-dependent AD.

Comments

This article was originally published in Neurobiology of Disease, volume 199, in 2025. https://doi.org/10.1016/j.nbd.2024.106570

Recommended Citation

Chandrashekar DV, Roules GC, Jagadeesan N, et al. Hepatic LRP-1 plays an important role in amyloidosis in Alzheimer's disease mice: Potential role in chronic heavy alcohol feeding. Neurobiol Dis. 2024;199:106570. https://doi.org/10.1016/j.nbd.2024.106570

Copyright

The authors

Creative Commons License

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