# Proteostasis dysregulation and the development of Alzheimer's-like neurodegeneration and dementia in Down syndrome

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $529,653

## Abstract

Down syndrome (DS) is a congenital condition resulting from partial or complete triplication of
human chromosome 21. Virtually all the subjects with DS develop widespread neuropathology
including amyloid- neuritic plaques, synaptic dysfunction and neurodegeneration, reminiscent of
Alzheimer's disease. While the extra copy of amyloid- precursor protein (APP) on chromosome
21 is thought to play a major role in the development of this type of pathologic phenotype in DS,
the underlying mechanisms responsible for these changes and their contribution to
neurodegeneration are still elusive. Compelling evidence supports the hypothesis that
physiological cellular proteostasis is of critical importance for neuronal health and that the
mammalian target of rapamycin (mTOR) is a master regulator of this vital cellular function.
However, while we know that the system is altered in DS we do not know whether it plays a
functional role in the pathogenesis of DS and the onset of neuropathology. In our preliminary data
we found that compared with healthy matched controls mTOR is hyperactive in selected brain
regions of DS patients. Importantly, we observed that in the same subjects the dysfunction directly
correlates with the pathology. Moreover, we show that mTOR is altered in the brain of a well-
established mouse model of DS, the Ts65Dn mice, at an early stage of the phenotype, and
associates with biochemical evidence of cell loss, suggesting a link between mTOR,
neuropathology and neurodegeneration in DS subjects. Taking into consideration the scientific
rigor of the previously published literature together with our recent findings we now propose a
novel working hypothesis: alteration of mTOR signaling pathway is responsible for the onset of
the neuropathologic DS phenotype and represents a novel and viable therapeutic target against
it in DS subjects. In this proposal, we will assess the temporal relationship between dysregulation
of mTOR in the brain of DS patients and the development of the neuropathology. We will then
focus on investigating early events responsible for this dysregulation in the same DS subjects.
Next, to prove its direct role in the pathogenesis of the syndrome, we will study the effect that
modulation of mTOR activity and expression levels has on behavior impairments and
neuropathology using in vivo models of DS. The results of our proposed studies will elucidate
early changes and the functional consequences of altered proteostasis secondary to dysregulated
mTOR in the development of the neuropathologic phenotype in individuals with DS. Importantly,
our findings have the potential to identify new therapeutic opportunities for delaying its onset and
/or halting its progression.

## Key facts

- **NIH application ID:** 10746844
- **Project number:** 5R01AG080817-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** DOMENICO PRATICO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $529,653
- **Award type:** 5
- **Project period:** 2022-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746844

## Citation

> US National Institutes of Health, RePORTER application 10746844, Proteostasis dysregulation and the development of Alzheimer's-like neurodegeneration and dementia in Down syndrome (5R01AG080817-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10746844. Licensed CC0.

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