# The intersection of Alzheimer's disease and ribosome biogenesis through Amyloid Beta Precursor Protein Binding Family B Member 1 (APBB1; FE65)

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $39,190

## Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and 
memory loss. It affects approximately 5.5 million Americans, and is the sixth-leading cause of 
death in the United States. The amyloid cascade hypothesis, caused by proteolytic processing of the 
amyloid precursor protein (APP), is one of the leading proposals for the cause of AD; however, 
drugs that target amyloid beta (Aβ) plaque formation have failed in clinical trials. The failure to 
produce a drug that treats the underlying cause of AD rather than its symptoms, suggests a gap in 
our understanding of the pathogenesis of this   disease. While APP is most notable as the precursor 
of Aβ, pathogenic processing also produces an  intracellular peptide (AICD) implicated in RNA 
polymerase II transcription with the adaptor protein Amyloid Beta Precursor Protein Binding Family 
B Member 1 (APBB1; FE65). Here, I present preliminary data that supports a novel role for APBB1 in 
the regulation of the essential process of making ribosomes. Furthermore, ribosome biogenesis has 
been associated with neuronal growth and viability, and dysfunction in this process has been 
observed in post-mortem AD patient brains. These observations have led some to propose a link 
between ribosome biogenesis and the pathogenesis of AD, and this proposal will explore this link 
through APBB1. First, I propose to probe the mechanism by which APBB1 regulates ribosome biogenesis 
in a cell culture system (Specific Aim 1). Second, I propose to test the extent to which APBB1 
regulates ribosome biogenesis in primary mouse neurons, and contributes to neuronal plasticity and 
viability (Specific Aim 2). I hypothesize that APBB1, in an AICD-dependent manner, regulates 
ribosome biogenesis as a cofactor for the transcription of nucleolar genes that are required for 
ribosome biogenesis. I also hypothesize that APBB1 is required for normal neuroanatomy including 
dendrite and dendritic spine density and morphology. Finally, I hypothesize that because of APBB1’s 
role in ribosome biogenesis, its depletion will trigger the nucleolar stress response leading to 
p53 stabilization and apoptosis. This proposal will both broaden our understanding of ribosome 
biogenesis in neurons, and also lend insight into the intersection between ribosome biogenesis and 
AD, opening new potential avenues for drug discovery.

## Key facts

- **NIH application ID:** 9833479
- **Project number:** 5F31AG058405-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Lisa Ogawa McLean
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,190
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9833479

## Citation

> US National Institutes of Health, RePORTER application 9833479, The intersection of Alzheimer's disease and ribosome biogenesis through Amyloid Beta Precursor Protein Binding Family B Member 1 (APBB1; FE65) (5F31AG058405-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9833479. Licensed CC0.

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