Reducing Tau as a Therapeutic Strategy for Improving Cognitive Dysfunction in Parkinson s Disease
Abstract
Scientific Objective: The goal of this proposal is to address the Parkinson s Research Program mission by determining if reducing the tau protein could be a treatment to prevent nonmotor symptoms of Parkinson s disease (PD) such as dementia, depression, and anxiety. Rationale: About 80,000 Veterans are being treated for PD and as many as one million people overall in the United States of America. Men and women in the Armed Forces may be more susceptible to developing this disease because of traumatic brain injury, exposure to neurotoxins, or prolonged stress. In addition to characteristic motor defects, up to 80% of PD patients develop dementia and mood disorders such as anxiety and depression. These symptoms contribute greatly to reduced quality of life for both the patient and caregiver, and can lead to institutionalization and even suicide. While some treatments help alleviate the symptoms of dementia and mood disorders, the effects are modest and do not prevent disease progression. The downstream mechanisms by which abnormal alpha-synuclein causes neuronal dysfunction and behavioral defects are unknown, but determining them is crucial for developing treatments for PD dementia. Studies of Alzheimer s disease (AD), the most common form of dementia, point to a protein called tau as one of the main culprits for causing cognitive problems. Exciting findings by our collaborator, Dr. Erik Roberson, show that reducing tau prevents cognitive dysfunction in mouse models of AD. Therapeutics to reduce tau are being developed for AD patients such as immunotherapy and antisense oligonucleotides that prevent tau expression. The contribution of tau in PD dementia is unknown. Studies that scan genomes of patients with sporadic PD consistently identify tau as a risk factor. These studies also consistently identify the protein, alpha-synuclein as a risk factor. Patients with mutations alpha-synuclein have profound depression and mood disorders. In addition, abnormal aggregates of alpha-synuclein are found in brain regions of PD patients that are critical for cognition. We propose that tau and alpha-synuclein interact to cause cognitive dysfunction and mood disorders in Parkinson s disease. We will use a novel mouse model in which formation abnormal alpha-synuclein aggregates can be induced in neurons that are similar to those found in PD brains. Hypothesis: The absence of tau will (1) prevent formation of abnormal pathologic alpha-syn aggregates and (2) prevent neuronal dysfunction and behavioral defects related to cognition and mood disorders that caused by these inclusions. Relationship of the proposed work to the Areas of Emphasis of this funding opportunity: Our proposed project will help determine whether reduction of tau is a rational therapeutic target for reducing pathological features of PD dementia, and for preventing cognitive dysfunction and mood disorders. Expected impact that the proposed work will have for improvement of therapy or quality of life for PD patients with non-motor manifestations: We hope that reducing tau will help prevent the progression of the disease and prevent development of cognitive dysfunction, depression, and anxiety. If so, the development of therapeutics targeting tau could alleviate a major burden and improve the quality of life for the patient and caregivers. How outcomes will be shared with other researchers and with the PD community: We will share our findings at national conferences and through publications that will have open access to the public. We also work closely with the Parkinson s Disease Association of Alabama, which can help communicate our findings to the PD community.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610677
Entities
People
- Laura A Volpicelli-Daley
Organizations
- United States Army
- University of Alabama at Birmingham