# Role of tanycytic LRP in Aβ clearance

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $437,500

## Abstract

This application corresponds to Notice of Special Interest: Alzheimer’s-focused administrative supplements for
NIH grants that are not focused on Alzheimer’s diseases. Alzheimer’s disease (AD) is a progressive
neurodegenerative disorder that is characterized by memory loss, impaired cognition and eventual functional
disability and death. AD affects an estimated 5.8 million people in the United States with half a million new cases
annually, and this number is anticipated to more than double within 30 years. Given the significant increase in
the prevalence of AD in the adult populations, identification of novel targets for treating and preventing AD and
its related dementias is urgently needed. The hallmark of AD pathogenesis is the accumulation of amyloid-
peptide (A) plaques between nerve cells in the brain. The A accumulation is the result of an imbalance of A
generation in amyloid precursor protein and its subsequent clearance. Impaired A clearance is predominantly
responsible for its accumulation in sporadic or the late-onset AD rather than A overproduction. The low-density
lipoprotein receptor-related protein-1 or -2 (LRP1 or LRP2) plays a role in eliminating A in the brain by promoting
A uptake and degradation in astrocytes, neurons and cerebrovascular smooth muscle cells, and A transcytosis
across the blood brain barrier. However, a major gap in understanding the central mechanisms underlying
LRP1/2-mediated A clearance has been a lack of knowledge regarding how LRP1/2 regulates A elimination
in the hypothalamic tanycytes. This could be due to a lack of an appropriate animal model that can study LRP1/2
function in the tanyctes in the context of A clearance in vivo. During the research period of the parent grant
(R01DK12302, Control of leptin transport system by LRP), we have generated the mice lacking LRP2 in the
tanycytes by breeding LRP2loxP/loxP with Rax-CreERT2 Knock-in mice (Rax-CreERT2; LRP2loxP/loxP). We are also
currently creating the mice lacking LRP1 in the tanycytes by breeding LRP1loxP/loxP with Rax-CreERT2 mice (Rax-
CreERT2; LRP1loxP/loxP). Using these models, we will test the novel hypothesis that LRP1/2 in the tanycytes of the
hypothalamus is necessary to clear A from the brain to the bloodstream and dysfunction of LRP1/2 in the
tanycytes leads to A accumulation in the brain, leading to AD. The data generated from these studies may offer
further insights into the pathogenesis of AD-related disorders and lead to new therapeutic targets for the
treatment of AD.

## Key facts

- **NIH application ID:** 10281970
- **Project number:** 3R01DK123002-02S1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** YOUNG-BUM KIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $437,500
- **Award type:** 3
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10281970

## Citation

> US National Institutes of Health, RePORTER application 10281970, Role of tanycytic LRP in Aβ clearance (3R01DK123002-02S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10281970. Licensed CC0.

---

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