# Investigating the vulnerability of WFS1-expressing excitatory neurons to tau pathology in early Alzheimer's disease.

> **NIH NIH K01** · OHIO STATE UNIVERSITY · 2020 · $124,308

## Abstract

Project Summary/Abstract
In the earliest stages of Alzheimer’s disease (AD), hyperphosphorylated and conformationally abnormal
(pathological) tau in the form of tangles, and selective neuronal loss have been found in the superficial layers of
the entorhinal cortex and in the CA1 of hippocampus. However, the precise neuronal cell types that accumulate
tangles and the biochemical pathways mediating this selective neuronal vulnerability are not known. We, and
others, have found that excitatory neurons in the EC and CA1 of hippocampus are particularly vulnerable to tau
pathology. Notably, Wolfram Syndrome 1 (WFS1), a transmembrane glycoprotein localized to the endoplasmic
reticulum (ER), is differentially expressed in excitatory neurons in those two regions. WFS1 dysfunction has been
found to contribute to neurodegeneration as well as stress and depression, possibly by regulating the
endoplasmic reticulum (ER) stress and/or the hypothalamic–pituitary–adrenal (HPA) axis. Based on these
observations, I hypothesize that tau pathology will reduce the expression of WFS1, resulting in ER and
cytosolic calcium dyshomeostasis, persistent activation of ER stress pathways and other as yet
unknown pathways, which in turn will exacerbate tau pathology, synaptic dysfunction, neuronal loss
and cognitive deficits. To test this hypothesis, this proposal will (1) determine if WFS1-expressing excitatory
neurons in the superficial layers of medial entorhinal cortex (MEC) and in the CA1 of hippocampus are vulnerable
to tau pathology in tau transgenic mice and in human AD; (2) investigate whether overexpression of WFS1
ameliorates ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and
cognitive deficits in rTg4510 tau mice; (3) explore whether conditional knockout of WFS1 in the brain exacerbates
ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and cognitive deficits
in rTg4510 tau mice; and (4) define the interaction between WFS1 and tau, and biochemical pathways in addition
to the ER stress pathways that underlie the vulnerability of WFS1-expressing excitatory neurons to tau pathology
in tau transgenic mice and in human AD. Identifying the molecular mechanisms underlying pathological tau-
mediated neuronal vulnerability and neurodegeneration in AD could aid in the discovery of novel drug targets
that can be targeted to protect vulnerable neurons. In addition, the approaches proposed to characterize cell
populations vulnerable to pathological proteins in AD can be applied to a wide range of degenerative diseases
that also show selective, cellular vulnerability.

## Key facts

- **NIH application ID:** 9889018
- **Project number:** 5K01AG056673-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Hongjun Fu
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $124,308
- **Award type:** 5
- **Project period:** 2018-11-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889018

## Citation

> US National Institutes of Health, RePORTER application 9889018, Investigating the vulnerability of WFS1-expressing excitatory neurons to tau pathology in early Alzheimer's disease. (5K01AG056673-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9889018. Licensed CC0.

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