# Structure and function of mammalian CPEB2 aggregates in normal and AD brain

> **NIH NIH R01** · STOWERS INSTITUTE FOR MEDICAL RESEARCH · 2024 · $465,534

## Abstract

Project Summary
The aggregate failure of pre-clinical and clinical trials in AD has demonstrated that an improved fundamental
understanding of memory and how the molecular components of memory are altered in the AD disease
process is necessary to develop effective treatment. The broad objective of the project is to identify the
biochemical substrates of long-lasting memories in mammals. The current proposal focuses on a family of
RNA-binding, cytoplasmic polyadenylation element binding protein (CPEB), that stabilizes memory in
invertebrates and mice. Remarkably, CPEB family protein forms non-disease-causing amyloidogenic
aggregates and aggregation of CPEB is necessary to stabilize memory. As amyloids are typically linked to
disease states, the question remains how similarly structured Aβ42 or Tau proteins can have opposing effects
on memory. Therefore, to develop a better understanding of the relationship between amyloids that support
memory and amyloids that disrupt memory, we will use a variety of techniques to solve the structure and
function of the CPEB family members, CPEB2 and CPEB3, in human and mice. In Aim 1, we will use cryo-
electron microscopy to solve the structure of CPEB aggregates from fresh human frontotemporal lobe tissue
collected from 25-50-year-old human subjects undergoing tissue removal under the standard of care for their
disease. These tissues would have been otherwise discarded. In Aim 2, mice lacking the ability to form
aggregates of CPEB2 and CPEB3 will be trained and tested in a one-trial inhibitory avoidance task to assay
their ability to form, maintain, and recall memory. In Aim 2 we will also investigate the consequence of CPEB2
and CPEB3 aggregation in translation of mRNA encoding synaptic proteins. The results would be the first to
provide direct structural analysis of a functional amyloid linked to memory in mammals, the structural
distinctions, if any, between functional and toxic amyloid in the human brain, and precisely link CPEB2 and
CPEB3 aggregation and activity to animals’ ability to form or stabilize memory. This knowledge would provide
the foundation to investigate in the future how toxic amyloids of Aβ42 or Tau specifically perturb memory.

## Key facts

- **NIH application ID:** 10792865
- **Project number:** 5R01AG066189-04
- **Recipient organization:** STOWERS INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Kausik Si
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,534
- **Award type:** 5
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10792865

## Citation

> US National Institutes of Health, RePORTER application 10792865, Structure and function of mammalian CPEB2 aggregates in normal and AD brain (5R01AG066189-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10792865. Licensed CC0.

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