# Project 2-Abeta-Dependent and  -Independent Roles of PS1

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $471,754

## Abstract

Population-based and translational studies provide evidence supporting the link between chronic
hyperactivity, amyloid abnormalities, and memory impairments. Importantly, network hyper-excitability and
reduced capacity of glutamate (Glu) transport is an early event and precedes the onset of Ab plaque/NFT
pathologies and memory impairment (Masliah et al.,1996; Quiroz et al.,2010). Furthermore, hyper-
synchronous network activity is particularly pronounced in families with presenilin (PS) mutations, with ~ 30%
of such AD patients displaying epileptic seizures (convulsive and non-convulsive), and ~75% suffering from
seizures in cases of the most aggressive PS variants (Larner and Doran, 2006; Kazim et al., 2017). During
the previous grant cycles we have established a unique PS1 conformation-sensitive FRET-based assay in
intact/live cells and demonstrated that fAD mutant PS1 adopts pathogenic conformation favoring generation of
the longer Ab species (Berezovska et al.,2005, Uemura et al.,2009), and showed that similar changes occur
in the wild type PS1 during aging and in sporadic AD (Wahlster et al., 2013). In our search for PS1-
modulating interactors we performed a proteomics screen of mouse brain lysates and identified GLT-1, a
major glutamate transporter in the CNS, as a novel PS1 binding partner. We have validated the PS1-GLT1
interaction on endogenous level in mouse brain and in primary astrocytes and neurons (Zoltowska et al.,
2018). Aim 1 will build on this observation, and will determine the physiological stimuli that modulate this
interaction in both astrocytes and neurons, verify if the interaction is limited to GLT1 glutamate transporter, will
establish the exact PS1/GLT1 interaction sites, and will determine whether fAD PS1 and APP eàg cleavage
cascade mutations (collaboration with Project 1) producing various naturally secreted Ab42/40/ 38/37 levels
and ratios affect the PS1-GLT1 binding. Next, we will examine if there is a functional crosstalk between the
PS1 and GLT1. Aim 2 will determine whether manipulation of the PS1/g-secretase expression level and
activity, allosteric modulation of the PS1 conformation (SGSMs, collaboration with Project 3) and/or change in
the Ab42/40/38/37 levels and ratios affect GLT1 localization, multimerization and, ultimately, glutamate
uptake. We will also detail the molecular mechanism(s) by which PS1 may modulate GLT1 cell surface
trafficking and activity. Conversely, Aim 3 will examine whether genetic or pharmacologic manipulation of the
GLT1 expression and binding to PS1 modifies PS1 conformation, APP processing/Ab generation, as well as
the integrity of dendritic spines/synaptic markers. Understanding the precise physiological and pathological
role of the novel PS1-GLT1 interaction is important because manipulation of this interaction may modify both
perisynaptic glutamate uptake and Ab generation, and thus translate into ”dual-effect” therapeutics, targeting
both glutamate overload and amyloid induc...

## Key facts

- **NIH application ID:** 10454841
- **Project number:** 5P01AG015379-24
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** OKSANA BEREZOVSKA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,754
- **Award type:** 5
- **Project period:** 1998-09-30 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454841

## Citation

> US National Institutes of Health, RePORTER application 10454841, Project 2-Abeta-Dependent and  -Independent Roles of PS1 (5P01AG015379-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10454841. Licensed CC0.

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