# Understanding the mechanism of rescue of Alzheimers disease by hematopoietic stem cell transplantation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $395,000

## Abstract

Project Summary
Alzheimer’s Disease (AD) is the most prevalent cause of dementia and the most common age-related
neurodegenerative disorder characterized by the progressive degradation of neurons, inflammation, decline in
memory and behavior, and the accumulation of β-amyloid (Aβ) plaque in the brain, particularly in the
hippocampus and cortex. The roles of microglia in AD are still a matter of intense debate in this disease. Using
the 5xFAD double transgenic mouse model of AD, which expresses mutant human APP and PSEN1, we
demonstrated that single systemic WT HSPC transplantation fully rescued AD leading to the preservation of
memory and neurocognitive performance, reduction of the β-amyloid (Aβ) plaque burden in hippocampus and
cortex, prevention of microgliosis and neuroinflammation, and preservation of the blood brain barrier (BBB)
integrity. We also showed that HSPCs differentiated into microglia-like cells in the brain, replacing up to 40% of
the endogenous microglia in the brain and with a resting and ramified phenotype. In contrast, transplanting
5xFAD mice with 5xFAD HPSCs had limited to no impact on any complications of AD. This work opens new
perspectives for utilizing HSPCs for the treatment of AD. However, the exact mechanism underlying the
significant therapeutic impact observed after transplanting WT HPSCs in the 5xFAD mice remains unclear.
Indeed, WT HSPC transplant fully prevented microgliosis, neuroinflammation and BBB disruption, despite partial
replacement of microglia by HSPC-derived microglia-like cells, suggesting a systemic beneficial impact of WT
HSPCs. In contrast, HSPCs isolated from 5xFAD mice exhibit limited to no therapeutic effect, suggesting that
5xFAD HSPCs and/or their progeny carry an inflammatory phenotype. This was supported by our preliminary
data showing significant decreases in memory and increases in locomotor activity in WT mice transplanted with
5xFAD HSPCs, resembling the behavioral patterns observed in 5xFAD mice. We will investigate the mechanisms
behind the impact of HSPCs, by first assessing the impact of 5xFAD HSPCs on the microgliosis and
neuroinflammation in WT mice and by examining the hematopoietic lineage profile in the peripheral blood to
verify if any skewing towards a specific lineage exists in the mice receiving the 5xFAD HSPCs. We will also
identify the genetic susceptibility that may exist in 5xFAD HSPCs or their hematopoietic progeny using RNAseq
and ATACseq. In addition, we will test the potential effects of mutated APP and/or PSEN1 on hematopoietic cell
lineages and determine whether they could directly trigger a pro-inflammatory state using CRISPR/Cas9
technology to knockout hmAPP and hmPSEN1 in murine Sca1+ HSPCs. Finally, we will determine the ability of
WT HSPCs to reverse neuroinflammation and preexisting complications in AD despite the presence of Aβ
aggregates by transplanting older 5xFAD mice (6 months of age) with WT HSPCs. This work should shed light
on the underlying mechan...

## Key facts

- **NIH application ID:** 10859495
- **Project number:** 1R01AG086443-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Stephanie Cherqui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859495

## Citation

> US National Institutes of Health, RePORTER application 10859495, Understanding the mechanism of rescue of Alzheimers disease by hematopoietic stem cell transplantation (1R01AG086443-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10859495. Licensed CC0.

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