# The impact of obesity-induced hepatic amyloid beta dysregulation on Alzheimer’s disease pathology

> **NIH NIH R21** · KECK GRADUATE INST OF APPLIED LIFE SCIS · 2024 · $405,849

## Abstract

PROJECT SUMMARY
 The long-term goal of this proposal is to determine how obesity modulates the liver-brain axis to induce
and/or promote Alzheimer’s disease (AD) pathology. Obesity and high fat/sugar diet are risk factors of AD, but
the mechanism is not completely understood. Obesity significantly affects the liver, causing fatty liver (liver
steatosis), which can progress to more severe liver diseases such as non-alcoholic steatohepatitis (NASH) and
cirrhosis. Our exciting recent data suggests that liver steatosis induced by obesity (ob/ob mice) or chronic alcohol
feeding causes the downregulation of hepatic lipoprotein receptor-related protein 1 (LRP1), the major hepatic
receptor that removes amyloid-β (Aβ) from the periphery, while simultaneously upregulates hepatic amyloid
precursor protein (APP), an important source of Aβ in the periphery and brain. The question of whether obesity-
induced steatotic liver, where APP is overexpressed and LRP1 in downregulated, can promote cerebral
amyloidosis and AD pathology, is unknown, merits further investigation, and is the focus of the current proposal.
This proposal will provide an integrated examination of how obesity-induced liver steatosis and hepatic Aβ
dysregulation affects cerebral Aβ levels to promote AD pathology through the following specific aims: Aim 1)
Examine the relationship between changes in peripheral and hepatic Aβ with brain Aβ load and AD pathology in
AD mice fed a high fat/high sucrose diet (Western diet; WD). Our working hypothesis is that dysregulation in
hepatic Aβ processing (increased APP and decreased LRP1) induced by WD increases hepatic, and thereby,
peripheral Aβ levels, that increase brain Aβ load to enhance AD pathology. By examining both human and mouse
Aβ and APP, and key proteins involved in Aβ homeostasis (BACE1, LRP1, IDE, and neprilysin) in the liver and
brain of WD-fed AD (APP/PS1) and WT mice, we will: a) determine if obesity-induced hepatic and peripheral Aβ
dysregulation correlates with brain Aβ load and AD pathology (tau phosphorylation, gliosis, neuronal loss,
cognition), and b) determine if obesity-induced hepatic Aβ dysregulation impacts healthy (WD-fed WT mice) and
pathologic (WD-fed APP/PS1 mice) brains differently. Aim 2) Determine the significance of hepatic APP and
LRP1 in regulating peripheral and brain Aβ, and AD pathology in AD mice. Our working hypothesis is that hepatic
APP overexpression and LRP1 silencing, as seen with liver steatosis, increase hepatic, peripheral and brain Aβ
levels to enhance AD pathology. The effect of specific targeting of hepatic APP (overexpression using adeno-
associated virus 8 (AAV8). TBG viral vector) and LRP1 (silencing using a AAV8.TBG.miRNA viral vector) on
peripheral and cerebral Aβ, and AD pathology in APP/PS1 mice will highlight the specific contributions of these
proteins in AD. The proposal will combine specialists in the areas of liver research with AD research to provide
an integrated examination of the liver...

## Key facts

- **NIH application ID:** 10790593
- **Project number:** 1R21AG085055-01
- **Recipient organization:** KECK GRADUATE INST OF APPLIED LIFE SCIS
- **Principal Investigator:** DERICK S HAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $405,849
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10790593

## Citation

> US National Institutes of Health, RePORTER application 10790593, The impact of obesity-induced hepatic amyloid beta dysregulation on Alzheimer’s disease pathology (1R21AG085055-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10790593. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*