# Mechanisms of TIMP2-mediated hippocampal revitalization in Alzheimer's disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $93,360

## Abstract

Project Summary/Abstract: Declining cognitive function is a hallmark feature of the aging process in the
elderly population. Since aging is the major risk factor for many leading causes of death, including dementias
such as Alzheimer's disease (AD), novel targets and strategies are needed as this population grows in the US
and beyond. Though the conventional view has held that plasticity is limited in the aged brain, emerging data
has challenged this notion, revealing that factors present within young blood are restorative for aged tissues
throughout the body while suggesting links between the systemic environment and aging- and Alzheimer's-
related changes in the brain. Aged mice sharing young blood via the parabiosis model or through plasma
transfer exhibit improved synaptic plasticity, dendritic spine number, and cognitive performance, which led me
to explore novel brain activities for systemic protein factors that may have relevance for AD. Our recently
published work uncovered tissue inhibitor of metalloproteinases 2 (TIMP2), a protein enriched in
developmentally-early human and young mouse plasma versus aged plasma that plays a surprisingly central
role in regulating synaptic plasticity within the hippocampus. I showed that treatment with TIMP2 significantly
revitalizes hippocampal function, as assessed by gene expression, long-term potentiation, and memory
performance in hippocampal-dependent behavioral tasks. Moreover, removing TIMP2 from hippocampal slices
dramatically reduced LTP and its loss in plasma ablated cognitive improvements conferred by young plasma.
This work has nonetheless left many fundamental questions open related to TIMP2's function within the
hippocampus, and its role in Alzheimer's disease remains unexplored. Recent work shows significantly
reduced TIMP2 levels in AD patients with vascular changes in CSF and altered levels of TIMP2 target MMP2
in plasma; our preliminary data support a perturbation of TIMP2 metabolism in plasma in mouse models of AD
pathology. We also find that TIMP2 expression decreases within dentate gyrus mossy cells important for the
LTP response. In this work, we will probe the mechanism by which CNS TIMP2 directly regulates hippocampal
function and the extent to which TIMP2 regulates hippocampal function in AD via changes in synaptic integrity
as well as amyloid-β (Aβ)-dependent mechanisms. We hypothesize that TIMP2 regulates synaptic function in
the normal hippocampus and is restorative in the context of AD pathology, primarily by acting to maintain
synaptic integrity. We will address this hypothesis in three major aims: (1) To assess functional effects in mice
in which hippocampal TIMP2 has been targeted and to evaluate the contribution of its source in mossy cells to
plasticity, (2) to assess the role of canonical and putative TIMP2 targets within the hippocampus, (3) and to
investigate the role of TIMP2 and related pathways in amyloid-independent and amyloid-dependent
mechanisms of AD patholog...

## Key facts

- **NIH application ID:** 10552139
- **Project number:** 3R01AG061382-03S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Joseph Michael Castellano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $93,360
- **Award type:** 3
- **Project period:** 2020-03-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10552139

## Citation

> US National Institutes of Health, RePORTER application 10552139, Mechanisms of TIMP2-mediated hippocampal revitalization in Alzheimer's disease (3R01AG061382-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10552139. Licensed CC0.

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