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

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $31,213

## Abstract

Summary of R01 Parent Grant, R01AG061382. Aging is the major risk factor for dementias such as Alzheimer’s
disease. Novel targets and strategies are needed as the number of adults over the age of 65 in the United States
is expected to reach 80 million by the year 2040. Though the conventional view holds that plasticity is limited in
the aged brain, emerging data have 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 disease-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 us to explore novel brain activities for systemic protein factors that may have relevance
for Alzheimer’s disease. Our recently published work uncovered that tissue inhibitor of metalloproteinases 2
(TIMP2), a protein enriched in developmentally early human and young mouse plasma versus aged plasma,
plays a surprising central role in regulating synaptic plasticity within the hippocampus (Castellano et al., 2017,
Nature). We 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 open many fundamental
questions related to TIMP2's function within the hippocampus, and its role in AD remains unexplored. Recent
work shows significantly reduced TIMP2 levels in Alzheimer’s disease 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 Alzheimer’s disease 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 Alzheimer’s disease 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 Alzheimer’s disease 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 amylo...

## Key facts

- **NIH application ID:** 10428067
- **Project number:** 3R01AG061382-02S1
- **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:** 2021
- **Award amount:** $31,213
- **Award type:** 3
- **Project period:** 2020-03-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428067

## Citation

> US National Institutes of Health, RePORTER application 10428067, Mechanisms of TIMP2-mediated hippocampal revitalization in Alzheimer's disease (3R01AG061382-02S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10428067. Licensed CC0.

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