# TRANSLATIONAL APPROACHES TO UNDERSTANDING THE FUNCTION OF HUMAN APP

> **NIH NIH R21** · CITY COLLEGE OF NEW YORK · 2020 · $431,750

## Abstract

Li, Christine
Project Summary
Deposition of beta-amyloid (Aβ)-rich dense plaques and the presence of hyperphosphorylated
tau neurofibrillary tangles are two postmortem criteria used in the diagnosis of Alzheimer's
disease (AD). Although Aβ is derived from a larger amyloid protein precursor (APP), the
function of APP and its various cleavage products and the targets/pathways in which they act
are still poorly understood. A family of APP-related proteins is present in mammals. Knockout
of the APP family in mice leads to postnatal lethality and type II lissencephaly, indicating that the
APP family has essential functions during development. sAPPα can modulate BACE activity
and levels of tau phosphorylation, suggesting that sAPPα can modulate levels two markers of
AD pathology. Like the mammalian APP family, the Caenorhabditis elegans ortholog apl-1 is
critical for survival; loss of apl-1 leads to larval lethality, which can be rescued by germline
transformation with an apl-1 genomic fragment or constructs encoding only the extracellular
domain of APL-1. We will leverage the strengths of C. elegans and mouse to identify the
function and cellular pathways in which APP acts and regulates. We have performed
biochemical and mutagenesis screens to identify protein interactors and suppressors of the apl-
1 lethality, respectively; our goal is to verify interacting proteins and identify the molecular
identity of the suppressor genes. Our second goal is to look at global changes in the whole
animal C. elegans transcriptome when APL-1 levels are perturbed in mutant and transgenic
strains. The C. elegans findings will be translated into the mouse system to determine whether
homologues have similar functions in APP biology. By using data uncovered in the C. elegans
system and testing them in the mouse system, we have a unique opportunity to identify
pathways in which APL-1/APP act, including pathways involved in the survival and proper
functioning of neurons. Our results may provide novel insights into how alterations in these
pathways may contribute to the pathologies seen in AD and highlight ways to formulate new
therapeutic strategies to effectively treat AD.

## Key facts

- **NIH application ID:** 9876328
- **Project number:** 1R21AG065890-01
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** CHRISTINE LI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876328

## Citation

> US National Institutes of Health, RePORTER application 9876328, TRANSLATIONAL APPROACHES TO UNDERSTANDING THE FUNCTION OF HUMAN APP (1R21AG065890-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9876328. Licensed CC0.

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