# Generating Exogenic Hippocampal Neural Cells via Blastocyst Complementation for Transplantation in Alzheimer's Disease.

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $385,000

## Abstract

SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is the leading cause of neurodegenerative disorders with over 5 million cases in the
U.S. This represents one of the most compelling health-related burdens facing our society in the near future.
Current approved therapies for AD include cholinesterase inhibitors to prevent the degradation of the
neurotransmitter acetylcholine, although they have modest benefit and are effective only during the early
stages of the disease process. The progressive dysfunction of the limbic system and loss of neurons in these
regions of the brain are responsible for the dramatic cognitive decline seen in this disease. Loss of cholinergic
neurons in the medial septal nucleus (MSN) and the nucleus basalis are observed in AD, in addition to the loss
of glutamatergic pyramidal neurons in the hippocampal formation. Transplantation of cholinergic neurons and
glutamatergic pyramidal neurons in rodents results in restoration of spatial learning and memory function.
Dysfunctional GABAergic interneurons within the hippocampal formation have been shown to cause
hyperactivity of neural circuits within the limbic system. Transplants of GABAergic interneurons into the
hippocampus of rodent models of AD demonstrate normalization of this hyperactivity and restoration of
learning and memory. In AD subjects with the APOE4 genotype, astrocytes derived from patients’ iPSCs
exhibit abnormal morphology. Transplants of astrocytes in other rodent models of neurodegenerative diseases
restore neurological function. The translation of cell replacement therapy to the clinic for treating AD requires a
source of authentic human progenitor cells. Recent studies utilizing blastocyst complementation in gene-
edited animals have resulted in the generation of authentic cells and organs such as islet cells and pancreas,
renal cells and kidney, and pulmonary cells and lung. We propose to use this approach to generate authentic
hippocampal GABAergic interneurons and astrocytes in mice for cell therapy in the APOE4 knock-in (KI)
mouse model of AD. A single Specific Aim is designed to characterize GABAergic neurons and astrocytes in
the brains of HHEX KO mouse fetuses following complementation with pluripotent murine stem cells. Two
Sub-Aims will (i) compare fetal GABAergic hippocampal interneurons and hippocampal astrocytes derived from
intra-species murine chimeras vs. wild-type fetuses; and (ii) transplant exogenic hippocampal GABAergic
interneurons and astrocytes derived from intra-species HHEX KO mouse chimeras into the brains of APOE4 KI
mice to determine efficacy of using exogenic neural cells as a source for transplantation. The results from
these studies will provide proof-of-principle that blastocyst complementation in gene edited animals may serve
as a platform for generating exogenic neural cells for transplantation in AD, and as a potential future human
therapeutic modality.

## Key facts

- **NIH application ID:** 10129456
- **Project number:** 3R01DK117286-03S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** WALTER C LOW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 3
- **Project period:** 2020-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129456

## Citation

> US National Institutes of Health, RePORTER application 10129456, Generating Exogenic Hippocampal Neural Cells via Blastocyst Complementation for Transplantation in Alzheimer's Disease. (3R01DK117286-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129456. Licensed CC0.

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