# Tau Pathology and Calcium Dyshomeostasis: Novel Imaging Approach and Therapy

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $466,125

## Abstract

Abstract:
 Perturbed neuronal calcium homeostasis has for many years been implicated in Alzheimer's disease,
and increased calcium influx has been linked to tau pathology, but this connection has not been well examined
in animal models. Our preliminary studies revealed abnormal calcium activity within soma and dendrites in
tauopathy mice compared to wild-type mice. Furthermore, we showed that the tau pathology-induced somatic
calcium dysregulation can be reversed by acute tau antibody administration. We propose to determine how
early this somatic and dendritic dysfunction occurs in tauopathy mice, its relationship to the degree of tau
pathology, and the relative contribution of intra- vs. extracellular tau to these neuronal impairments. Towards
this objective, the following specific aims are proposed: 1) To determine age-dependency of functional deficits
within soma and dendrites in cortical tauopathy neurons with in vivo two-photon calcium imaging; 2) To
determine the relative contribution of extracellular tau to neuronal calcium dysregulation compared to the total
pool of tau within the brain that is accessible to antibody-mediated clearance. We hypothesize that calcium
dyshomeostasis occurs earlier in dendrites than in soma, because the latter likely requires more severe
neuronal dysfunction to manifest. In addition, we hypothesize that targeting both intra- and extracellular tau will
be more efficacious than only targeting tau extracellularly. Our preliminary data indicates that in vivo two-
photon imaging is a sensitive and comprehensive approach, within a short timeframe, to provide mechanistic
insight into how tau immunotherapies work to benefit neuronal function. Using this approach, we will examine
the efficacy of a tau antibody that targets tau intra- and extracellularly vs. an engineered version of the same
tau antibody that is not taken up into neurons, and can only target tau extracellularly. This will allow us to
determine the relative contribution of these two pools of tau on neuronal dysfunction. Overall, these studies
should provide important functional and mechanistic insight into tau pathogenesis in Alzheimer's disease and
related tauopathies.

## Key facts

- **NIH application ID:** 10143615
- **Project number:** 1R21AG069475-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Einar M Sigurdsson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,125
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143615

## Citation

> US National Institutes of Health, RePORTER application 10143615, Tau Pathology and Calcium Dyshomeostasis: Novel Imaging Approach and Therapy (1R21AG069475-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143615. Licensed CC0.

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