# Linking NPTX2 and Tau pathophysiology in AD

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $249,047

## Abstract

PROJECT SUMMARY
Tau pathology in Alzheimer’s disease (AD) is linked to neuronal activity in multiple ways, including an effect of
activity to increase tau phosphorylation [1], tau spread between neurons, and tau shedding into the CSF [2], and
activity inhibition reduces tau pathology [3]. NPTX2 (Neuronal Pentraxins 2) is an immediate early gene (IEG)
that acts specifically at excitatory synapses on parvalbumin interneurons (PV) to regulate circuit inhibition and is
prominently down-regulated in the brain of individuals with AD [4]. During its normal function, a portion of synaptic
NPTX2 is shed into the cerebrospinal fluid (CSF) where levels in human subjects inversely correlate with
cognitive performance and hippocampal volume in MCI and AD [4-6]. One consistent observation in these
studies is that a ratio of CSF NPTX2 and tau or ptau prominently increases diagnostic performance [4-6]. This
suggests an important relationship between CSF NPTX2 and tau/ptau in AD. NPTX2 is generated by pyramidal
neurons (Py) throughout the forebrain and is trafficked along axons to presynaptic sites where it is exocytosed
in response to Py activity and functions specifically at excitatory synapses on PV to strengthen the excitatory
drive of PVs, thereby enhancing inhibition within the circuit [7, 8]. Consistent with these synaptic effects, NPTX2
loss of function results in increased Py activity and reduced gamma power, and these effects are amplified by
Aß amyloidosis [4]. These observations focus attention on potential interactions between NPTX2 loss of function
and tau pathophysiology. To examine the interaction of tau with NPTX2, we will use a newly established rat AD
model (TgF344-AD) that expresses human FAD mutations including APP (APPswe) and presenilin 1 (PSΔE9)
and mimics human disease by developing tau pathology without requiring mutation of tau [9]. Aim 1 will develop
novel tools to image tau accumulation in vivo using 2-photon microscopy. Fluorescent tau indicators, termed
Tau1 and Tau 2, will be evaluated for detection of tau accumulations in TgF344-AD rats following either i.v. or
local injection of the reporters into the brain using a novel perforated cranial window. In vivo 2-photon images of
tau will be correlated with histopathologically imaged tau. Aim 2 will examine the impact of conditional deletion
of NPTX2 in TgF344-AD rat neocortex on tau accumulation and cellular localization and correlate these
parameters with the activity of Py and PV neurons using cutting-edge multi-color longitudinal 2 photon imaging.
The proposed research will develop methods to image pathologic tau accumulation in vivo and test the
association of pathological forms of tau with NPTX2 loss of function and resulting changes in brain activity.

## Key facts

- **NIH application ID:** 10807785
- **Project number:** 1R21AG085577-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Seung-Eon Roh
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,047
- **Award type:** 1
- **Project period:** 2024-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807785

## Citation

> US National Institutes of Health, RePORTER application 10807785, Linking NPTX2 and Tau pathophysiology in AD (1R21AG085577-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10807785. Licensed CC0.

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