# Restorative gene therapy on hippocampal spino-dendritic abnormalities: a focus on Alzheimer’s disease

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2021 · $236,833

## Abstract

SUMMARY/ABSTRACT
There are currently no effective treatments to prevent, delay, or reverse the memory deficits and
neuropathological alterations—specifically dendritic damage and synaptic loss—associated with Alzheimer’s
disease (AD). Without an effective treatment soon, many more millions of older adults will continue to suffer from
this devastating disease. Thus, there is a critical need to investigate novel molecules/mechanisms involved in
the maintenance and regeneration of dendrites and their spines for the purpose of rescuing cognitive functions.
The long-term goal is to develop an effective treatment to prevent or halt AD. The overall objective of this
application is to determine the potential of a recently identified phosphoprotein, CRMP3 (collapsing response
mediator protein 3), to ameliorate dendritic abnormalities and/or rescue memory deficits in two distinct mouse
models with AD-like characteristics. 3xTg-AD mice are one of the most commonly used mouse models of AD.
They harbor 3 mutations (APP, PSEN1, and MAPT) that result in the accumulation of plaques and tangles,
abnormalities in dendritic and synaptic structures, and significant cognitive impairments. CRMP3-/- mice exhibit
dystrophic hippocampal dendrites and profoundly impaired synaptic plasticity (LTP). Importantly, overexpressing
the CRMP3 protein in hippocampal neurons, in vitro, dramatically enhances dendritic formation. The central
hypothesis is that over-expressing CRMP3, in vivo, will prevent further dendritic degeneration and/or evoke
dendritic regrowth and remodeling of spines in otherwise degenerating hippocampal neurons, thus preserving
or rescuing memory function. This hypothesis has been formulated on the basis of strong preliminary data
produced in the applicants’ laboratories. This hypothesis will be tested by pursuing two specific aims: 1)
Determine the extent to which in vivo over-expression of CRMP3 enhances hippocampal dendritic complexity
and spine structure in CRMP3-/- and 3xTg-AD mice; and 2) Determine the extent to which in vivo over-expression
of CRMP3 affects hippocampal-dependent memory function in CRMP3-/- and 3xTg-AD mice. Under the first aim,
adeno-associated viral vector serotype 9 (AAV9) gene therapy will be used to overexpress CRMP3 in the
hippocampus of these two AD-like mouse models and its effects on AD-associated spino-dendritic abnormalities
will be examined. Under the second aim, the extent to which CRMP3 gene therapy can ameliorate contextual
and spatial memory function will be measured using two behavioral paradigms (contextual fear conditioning and
Morris water maze). The approach is innovative because CRMP3 is a little-known protein with tremendous
potential to repair and regenerate dystrophic and damaged spines and dendrites. The proposed research is
significant because it is expected to advance knowledge about a protein with the robust capacity to slow, halt,
or even reverse early AD processes that may be precursors to deep dementia, t...

## Key facts

- **NIH application ID:** 10140821
- **Project number:** 1R21AG071133-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** RUTH M BARRIENTOS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $236,833
- **Award type:** 1
- **Project period:** 2021-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140821

## Citation

> US National Institutes of Health, RePORTER application 10140821, Restorative gene therapy on hippocampal spino-dendritic abnormalities: a focus on Alzheimer’s disease (1R21AG071133-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10140821. Licensed CC0.

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