# Cortical Mechanisms in Lewy Body Dementia

> **NIH NIH K08** · UNIVERSITY OF IOWA · 2022 · $187,164

## Abstract

Project Summary/Abstract
Lewy Body dementias are a common form of degenerative dementia. These diseases are debilitating, causing
visual hallucinations, fluctuations in consciousness, disturbed sleep, falls, and depression, all leading to loss of
independence, disability and significant caregiver burden. In these disorders, the protein alpha-synuclein
accumulates into pathognomonic “Lewy bodies” and “Lewy neurites”. Patients with Lewy Body dementia have
diffuse intracellular cortical Lewy Bodies, cortical thinning, and loss of neuronal anatomy, including dendrites
and spines. These changes may occur due to altered calcium regulation caused by alpha-synuclein oligomers,
which accumulate under pathologic conditions. Overexpression of alpha-synuclein in humans leads to familial
disease, including dementia, and therefore provides a useful model to evaluate the mechanisms of neuronal
dysfunction. This proposal uses viral overexpression of alpha-synuclein in the cortex of mice to examine the
pathological changes occurring in cortical neurons as the protein accumulates. Specifically, this proposal first
tests the hypothesis that local alpha-synuclein accumulation induces dendritic spine instability, leading to
dendritic spine loss overtime. This is tested using longitudinal, live animal, 2-photon imaging to repeatedly
observe individual dendritic spines as pathology develops. Secondly, this proposal evaluates if calcium
dynamics change over time due to alpha-synuclein accumulation, a potential mechanism for network
dysfunction and anatomical pathology. The findings from this proposal will demonstrate how a-synuclein exerts
its pathological effect in cortical cells and evaluate a mechanistic model based on Ca2+ dynamics. By including
evaluation over time, these studies are more likely to model aspects of human disease and lead to translatable
treatments. As a career development grant this proposal is ideal; it leverages the applicant’s past skills in 2-
photon imaging of dendritic spines with a complementary, mechanistic and computational approach using Ca2+
imaging, which is novel to the applicant. The institution is dedicated to providing the support and resources
necessary for the applicant’s success. There is strong mentorship available in areas of research proposed,
supplemented with instruction by consultants and formal workshops. Together, this will provide key training
opportunities that will advance the applicant’s career as an academic physician-scientist focusing on
understanding and treating Lewy Body Dementias.

## Key facts

- **NIH application ID:** 10409753
- **Project number:** 5K08NS109287-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Georgina Aldridge
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $187,164
- **Award type:** 5
- **Project period:** 2018-09-18 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409753

## Citation

> US National Institutes of Health, RePORTER application 10409753, Cortical Mechanisms in Lewy Body Dementia (5K08NS109287-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10409753. Licensed CC0.

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