# Evaluation of the lysosomal protease tripeptidyl peptidase 1 as a potential therapeutic for Alzheimer Disease

> **NIH NIH R21** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2020 · $238,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite extensive efforts and investment, there is no cure for Alzheimer disease (AD) or effective treatment to
slow progression of this devastating disorder. One potential therapeutic strategy is to promote degradation of
amyloid beta (Aβ), whose accumulation in the brain is associated with and may be integral to the disease
process. We have recently obtained strong evidence that the lysosomal protease tripeptidyl peptidase 1 (TPP1)
plays an important role in degradation of Aβ fibrils. We hypothesize that increasing activity of TPP1 will promote
degradation of Aβ, slowing or preventing its accumulation in the brain with subsequent therapeutic benefits for
AD. We will test this hypothesis using two complementary approaches in the J20 mouse, a transgenic AD model
that overproduces human Aβ and exhibits age-dependent plaque accumulation and cognitive deficits.
First, in a genetic proof-of-principle study, we will cross the J20 mouse with our newly created transgenic mouse
that constitutively overexpresses mouse TPP1 (~10-fold higher activity than endogenous levels). Second, we
will use a peptide-mediated method to deliver recombinant human TPP1 protein from the bloodstream across
the blood-brain barrier into the brain of the J20 mouse. Treatment groups and controls will each contain 30
animals with equal numbers of males and females. For both Aims, we will employ identical approaches to
evaluate the effect of elevated TPP1 activity on the AD phenotype. At the age of seven months, we will analyze
treated mice and controls using the Morris water maze, novel object recognition and fear conditioning assays.
At eight months, the mice will be euthanized and levels of soluble and insoluble Aβ measured in brain extracts
by ELISA and plaque measured in cortex and hippocampus by immunohistochemistry.
If TPP1 augmentation has a positive effect on AD phenotype in the J20 mouse, this would provide a strong
rationale to explore this further with the long-term goal of developing an effective therapy for AD. Additional
studies in laboratory animals would be required prior to initiation of trials in humans. Looking forward, it is worth
noting that targeting protein-based drugs across the blood-brain and/or cerebrospinal fluid-brain barrier
continues to be a major obstacle for the development of biologic therapeutics for AD and other neurological
disorders. However, in the case of TPP1, delivery of recombinant protein to the brain by intracerebroventricular
administration has been approved by both the Federal Drug Administration and the European Medicines Agency
for treatment of a neurodegenerative lysosomal storage disease. A similar delivery method should be feasible
for AD and may allow repurposing of an existing drug.

## Key facts

- **NIH application ID:** 9994158
- **Project number:** 5R21AG064595-02
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** PETER LOBEL
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $238,500
- **Award type:** 5
- **Project period:** 2019-08-15 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994158

## Citation

> US National Institutes of Health, RePORTER application 9994158, Evaluation of the lysosomal protease tripeptidyl peptidase 1 as a potential therapeutic for Alzheimer Disease (5R21AG064595-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9994158. Licensed CC0.

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