# The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $563,692

## Abstract

PROJECT SUMMARY/ABSTRACT
 Individuals at risk of Alzheimer’s disease (AD) undergo a long, asymptomatic phase of disease
progression that is characterized by the gradual accumulation of pathology in the absence of apparent
cognitive deficit. Down syndrome (DS) patients represent a population at high risk of AD with complete
penetrance of AD pathology in the majority of DS subjects, making DS an outstanding natural genetic model
for the study of neuropathological mechanisms of AD and for identifying potential AD biomarkers. Given the
current limitations in reliable early diagnostic tools, the discovery of biomarkers signalling the evolution of
Alzheimer’s disease pathology in individuals at risk, including those with DS, is of utmost clinical relevance.
 The overall goal of the current proposal is to investigate novel, uncharacterized biomarkers at
the earliest preclinical stages of AD in DS. To achieve this goal, a collaborative effort will integrate data from
post-mortem brain studies, primary human cell cultures studies, and biological fluids (plasma and CSF) studies
in a large well-characterized cohort of DS and matched control subjects.
 The central hypothesis of the proposal is that the early accumulation of intracellular amyloid beta
peptide (Aβ) in DS brains will induce CNS inflammation accompanied by NGF metabolic dysfunction
prior to extracellular amyloid plaque deposition. Furthermore, the CNS compromise of NGF
metabolism should be detected in DS body fluids at ‘incipient’ stages of the AD pathology, before the
presentation of overt dementia.
 To test the stated hypothesis, three Specific Aims will be accomplished: Aim 1: To explore the
occurrence of a CNS pro-inflammatory process and NGF dysfunction throughout the lifespan in DS. Using
post-mortem DS brains at different ages, the appearance of inflammation and NGF dysfunction in DS will be
investigated to temporally reconstruct the evolution of AD pathogenesis. Aim 2: To investigate molecular
mechanisms that link early AD pathology in DS with neuroinflammation and NGF metabolic dysfunction using
fetal human primary cortical cultures. These studies will complement Aims 1 and 3 and will elucidate molecular
pathways underlying early AD pathogenesis. Aim 3: To analyze the expression of Aβ, tau, NGF-related and
inflammatory markers in matched plasma and CSF samples from DS subjects across the lifespan. These
studies will test whether markers investigated in Aims- 1 and -2 are reflected in matched plasma and CSF
samples from DS versus control subjects.
 This multi-PI multidisciplinary proposal will reveal fundamental molecular pathobiological mechanisms
for AD in DS, it will identify biomarkers, and it will assist in the prediction of the onset and trajectory of
dementia. In addition, the planned studies will likely lead to the identification of novel therapeutic targets in both
DS individuals and sporadic AD populations.

## Key facts

- **NIH application ID:** 10250064
- **Project number:** 3RF1AG056850-01A1S2
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** JORGE A BUSCIGLIO
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $563,692
- **Award type:** 3
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250064

## Citation

> US National Institutes of Health, RePORTER application 10250064, The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome (3RF1AG056850-01A1S2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10250064. Licensed CC0.

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