# Intramuscular delivery of recombinant AAV expressing EpoR76E improves memory and is neuroprotective in 5xFAD transgenics

## TL;DR

A modified form of erythropoietin delivered via a virus improved memory and protected brain cells in a mouse model of Alzheimer's disease.

## Contribution

A modified erythropoietin (EpoR76E) delivered via AAV shows neuroprotection and cognitive benefits in Alzheimer's models without hematopoietic side effects.

## Key findings

- AAV.EpoR76E prevented cognitive decline in 5xFAD Alzheimer's mice.
- Treatment preserved synaptic proteins and reduced amyloid-β levels.
- Neuroprotection was observed in key brain regions like the medial septum.

## Abstract

Converging evidence suggests that erythropoietin (Epo) may be effective in alleviating symptoms of many neurological conditions, including traumatic brain injury and neurodegenerative disorders. However, a limitation to its use as a therapeutic agent is the risk associated with stimulation of hematopoietic pathways. To overcome this issue, we used a recombinant adeno-associated viral vector (AAV) designed to express a modified form of erythropoietin devoid of hematopoietic activity, EpoR76E. Our previous research showed that AAV.EpoR76E prevented motor impairments and mitigated loss of dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. In the present study, a single intramuscular injection of AAV expressing EpoR76E prevented cognitive decline in the 5xFAD transgenic model of Alzheimer’s disease. Consistent with this, AAV-EpoR76E prevented the age-related loss of pre-and post-synaptic proteins synaptophysin and PSD-95 normally seen in 5xFAD transgenics. Additionally, the treatment reduced soluble and aggregated amyloid-β levels in 5xFAD mice, and prevented the loss of neurons in the medial septum and vertical limb of the diagonal band, the primary cholinergic projections to the hippocampus. Together, these results suggest that AAV-EpoR76E might represent a novel therapeutic approach for Alzheimer’s disease and other neurodegenerative disorders.