# Project 2: Co-pathogenic Interactions between ApoE Isoforms and Abeta in Neural Network Dysfunction of Alzheimer's Disease

> **NIH NIH P01** · J. DAVID GLADSTONE INSTITUTES · 2021 · $921,999

## Abstract

PROJECT 2 – SUMMARY
Numerous lines of evidence suggest that human amyloid precursor protein/amyloid b (APP/Ab), apoE4, and the
microtubule-associated protein tau contribute to Alzheimer’s disease (AD), but their pathogenic interactions are
largely unknown. Reducing Ab accumulation in the brain was considered the most reasonable therapeutic
strategy for AD, but multiple clinical trials of this approach have failed, suggesting that the pathophysiology of
AD is much more complex than anticipated and that the pathogenic interactions of AD-relevant proteins need to
be better understood. To decode the multifactorial etiology of AD at physiological levels of expression, we will
study newly developed knock-in (KI) mouse models of late-onset (LOAD) and familial (FAD) AD without
transgene overexpression and focus on the pathogenic interactions between Ab, apoE, and tau. To simulate
LOAD, we will use KI mice that express humanized wildtype Ab without FAD mutations (ApphAβWT/hAβWT; referred
to as Aβ mice), human apoE isoforms (APOEE2/E2, APOEE3/E3, and APOEE4/E4; E2, E3, and E4 mice), and human
wildtype tau (MAPTWT/WT, TAUWT mice). To simulate FAD, we will use KI mice that express humanized wildtype
Ab with the Swedish and Iberian FAD mutations (AppNL-F/NL-F; ↑Ab mice), human apoE isoforms (E3 and E4), and
human wildtype tau (TAUWT). Thus, we propose to study the physiological and endogenous interactions of human
Ab, apoE isoforms, and tau in vivo that contribute to AD-related abnormalities in neural network activity, cognitive
functions, gene expression, and histopathology using state-of-the-art in vivo electrophysiological, optogenetics,
and behavioral approaches. We will focus on mechanisms of altered neural network dysfunction, since they
closely relate to brain and cognitive functions and are disrupted early in AD pathogenesis.
In Aim 1, we will determine pathogenic interactions of Ab, apoE isoforms, and tau contributing to altered neural
network activity (Aim 1a) and behavioral deficits (Aim 1b) in LOAD and FAD KI mice during disease progression
using wireless long-term EEG/EMG recordings and standard and machine learning behavioral approaches. In
Aim 2, we will determine pathogenic interactions of Ab and apoE4 contributing to cell and circuit function
impairments in LOAD and FAD KI mice in vivo (Aim 2a, b) and if optogenetic activation of specific interneuron
cell types reverses AD-related abnormalities (Aim 2c). We will use in vivo LFP and multi-unit recordings and
optogenetic approaches in behaving mice to identify cell type and circuit-level mechanisms of network
dysfunction. In Aim 3, we will determine pathogenic interactions of Ab, apoE isoforms, and tau contributing to
AD-related pathology (Aim 3a) and scRNA-seq transcriptome changes (Aim 3b) in LOAD and FAD KI mice. We
will perform AD-related pathological and scRNA-seq transcriptomics analyses in functionally characterized mice
(in vivo physiology and behavior) from Aims 1 and 2 to identify pat...

## Key facts

- **NIH application ID:** 10271127
- **Project number:** 1P01AG073082-01
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Jorge J Palop
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $921,999
- **Award type:** 1
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271127

## Citation

> US National Institutes of Health, RePORTER application 10271127, Project 2: Co-pathogenic Interactions between ApoE Isoforms and Abeta in Neural Network Dysfunction of Alzheimer's Disease (1P01AG073082-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10271127. Licensed CC0.

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