# Neurovascular unit dysfunction in Down syndrome revealed by TBI

> **NIH NIH RF1** · UNIVERSITY OF COLORADO DENVER · 2022 · $2,601,812

## Abstract

PROJECT SUMMARY.
Down syndrome (DS) is the most common genetic cause of intellectual disability and results from triplication of
chromosome 21 (Hsa21), also known as trisomy 21 (T21). Individuals with DS demonstrate cognitive deficits
and are at an increased risk of developing central nervous system (CNS) conditions, including neurological and
psychological impairment, and Alzheimer’s disease (AD). With the exception of AD, which is linked to
overexpression of the Has21-encoded amyloid precursor protein, the mechanisms underlying these CNS
conditions remain largely unclear. This knowledge gap is hindering therapies for these conditions. People with
DS are also exquisitely sensitive to environmental and social risk factors such as higher susceptibility to serious
infection and to stress-triggered regression, consistent with the notion that external factors can be combined with
T21-related genetic factors to reveal otherwise subtle pre-exiting defects in individuals with DS. Our exciting
preliminary findings indicate that mild traumatic brain injury (mTBI) is a sensitizing stressor that reveals T21-
associated neurovascular defects. mTBI results from a mild blow to or a sudden jolt of the head leading to
neuroinflammation and oxidative stress that damage brain cells. It is a serious public health concern on its own,
affecting ~3 million Americans each year with ~20% of them experiencing long-term neurological deficits. While
examining the interaction between DS and mTBI, we recently uncovered a striking susceptibility of the Dp16 DS
model mouse to mTBI-induced neurological and cognitive impairments. Young Dp16 mice exhibit a longer period
of coma immediately after the head injury and display more severe sensorimotor and cognitive deficits even days
later. Surprisingly, older Dp16 mice, but not age-matched controls, sustain severe post-injury intracerebral
hemorrhage, indicating a cerebrovascular fragility that worsens with age. Moreover, expression of CtBP2, a
proinflammatory transcriptional coactivator that is induced by mTBI, is elevated in the brains of injury-free Dp16
mice. These findings suggest the presence of T21-associated alterations in neuronal, glial, and vascular cells,
which are the building blocks of the neurovascular unit (NVU). We postulate that T21 promotes NVU dysfunction
through an interplay among developmental abnormalities, immune dysregulation, and oxidative stress, which
predisposes the DS brain to a higher risk of TBI-induced long-term impairment. To test this hypothesis, we will
firs establish how T21-related cellular defects and/or specific candidate genes exacerbate mTBI-induced
sensorimotor and cognitive impairments (Aim 1). We will then define the cerebrovascular abnormalities in DS
and aging brains with the aid of mTBI (Aim 2). We envision that these studies will help establish the molecular
and cellular basis for DS-associated CNS conditions. The combined expertise in TBI, cerebrovascular function,
DS mouse models, a...

## Key facts

- **NIH application ID:** 10518832
- **Project number:** 1RF1NS128739-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MINGXIA HUANG
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,601,812
- **Award type:** 1
- **Project period:** 2022-09-07 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518832

## Citation

> US National Institutes of Health, RePORTER application 10518832, Neurovascular unit dysfunction in Down syndrome revealed by TBI (1RF1NS128739-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10518832. Licensed CC0.

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