# Altered Copper Neuronal Transport and Alzheimer's Disease

> **NIH NIH R36** · LOMA LINDA UNIVERSITY · 2020 · $68,604

## Abstract

Project Summary
I hypothesize that apoplioprotein E (APOE)-associated dysregulation of hippocampal copper
(Cu) metabolism is a key step in Alzheimer’s disease (AD) pathogenesis. This project will
approach this topic from two specific aims: 1) establish the relationship between copper (I)
cation distribution and AD pathology, and 2) study the APOE4-alteration effect on hippocampal
synaptic pruning and Cu deposition in the mouse hippocampus. This approach is innovative in
its use of two newly developed technologies that will be used to investigate hippocampal Cu
dysregulation, synaptic density and its relation to the toxic APOE4 allele. The CRISP-17
fluorescent probe is a state-of-the-art tool in histochemical Cu localization, with a specificity for
monovalent Cu far beyond other existing probes. CRISP-17 will visualize Cu distribution in post-
mortem human AD hippocampal brain tissue. Synaptosome fractions will be isolated and
measured for Cu using atomic emissions spectroscopy. Cu transport proteins will be
downregulated in SH-SY5Y neuroblastoma cells, with effects on Cu deposition being analyzed
using the fluorescent probe and synaptosome fractions being isolated and measured for Cu
levels. Synaptic density will be studied in APOE4 knock-in mice and compared with the
neuroprotective APOE3 knock-in mice with PET scans targeting the SV2A synaptic protein.
Mouse brain tissue will then be taken and histochemically analyzed for monovalent Cu using
CRISP-17, verifying this relationship in the animal model. We expect to find similarly that
APOE4 knock-in mice have a greatly reduced synaptic density when compared to the
neuroprotective APOE3 knock-in mice, with the mouse hippocampus also exhibiting a decrease
in Cu distribution. These aims are designed to further the goals of the NIH by investigating a
possible pathway to AD, a disease whose pathogenesis not yet fully defined.

## Key facts

- **NIH application ID:** 10038512
- **Project number:** 1R36AG064148-01A1
- **Recipient organization:** LOMA LINDA UNIVERSITY
- **Principal Investigator:** Nicholas Sanchez
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $68,604
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10038512

## Citation

> US National Institutes of Health, RePORTER application 10038512, Altered Copper Neuronal Transport and Alzheimer's Disease (1R36AG064148-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10038512. Licensed CC0.

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