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Sleep problems, such as wakefulness at night and daytime napping, are common in patients with Alzheimer disease (AD). While sleep disturbances are often considered to be a consequence of neurodegeneration, we are taking another look. Data suggest that sleep disturbances occur very early in the course of the disease and might possibly contribute to AD-associated pathologies as well as the onset of cognitive symptoms including mild cognitive impairment (MCI). By switching sleep on and off, we will be able to assess whether sleep disturbances, such as unusual sleep duration and sleep fragmentation, are an early factor that contributes to the risk of developing AD. 

Alzheimer’s disease (AD) is thought to be caused in part by the build-up of amyloid beta (Aβ) protein in the brain. Although the basic process that generates Aβ is well studied, an important unresolved question is what factors turn this process on and off. We have identified for the first time serine/threonine-protein kinase PLK2, an enzyme that in humans is encoded by the PLK2 gene, as a candidate factor that stimulates Aβ production. Here we will examine the role of PLK2 in disease progression using mouse models of Alzheimer's. These studies are critical for understanding the mechanisms underlying Alzheimer's and for advancing new targets for drug therapies.

Human genetic studies strongly point to apolipoprotein E (APOE) and microglia (the immune cells of the brain) as,  respectively, the most important gene and cell type in the chain of events leading to Alzheimer’s disease(AD), a common disorder in the elderly in which the brain is damaged and memories falter. In normal conditions, microglial cells do not make APOE; however, in disease conditions, they sense the brain damage and respond by churning out APOE. It is unclear why this occurs. The goal of this project is to answer this question in a mouse model where the APOE gene is switched off in microglia.

The biological molecular mechanisms controlling the growth of connections in the central nervous system (CNS) are still poorly understood. The inability of the eye to regenerate such connections to the brain is the key reason why vision is lost from optic nerve damage, which can happen in a disease such as glaucoma, cannot be restored. We propose to identify novel biological regulators of the intrinsic ability of the retinal cells to regrow such connections between the eye and the brain. These studies could lead to the development of therapeutics for restoring simple visual abilities to those who became blind due to angle-closure glaucoma, and possibly other types of glaucoma.

My research aims to determine whether depletion of TAR DNA-binding protein 43 (TDP-43) in neurons contributes to pathological conversion of tau or accelerates tauopathy, a critical driver of neuron loss and cognitive decline in sporadic Alzheimer’s disease (AD). The pathological alteration and aggregation of tau protein (called tauopathy) is arguably the most important alteration in AD, as it shows the strongest association with the loss of brain cells and memory. Many studies have shown TDP-43 abnormality in 30-70% of AD cases, and that these cases show worsened memory loss. The aim of our study is to find out if TDP-43 loss plays a role in the initiation or acceleration of tauopathy in AD. Once we know what drives the changes in tau, we can halt or slow the progression of this disease. 

Brain cells are made up of many different proteins that help them work correctly. Bad proteins can build up in the brain cells and cause them to become sick and die in Alzheimer’s disease. We want to study how a group of proteins known as ribonucleic acid (RNA) processing factors may cause bad proteins to build up in the cells. Results from the study may show us a new way to slow or stop the brain cell injury in Alzheimer’s disease (AD).

Alzheimer’s disease (AD) is a devastating neurological disease for which there currently are no effective therapeutics. Critical to the development of therapeutics that may treat and even cure AD is an understanding of the dynamics (the change over time) of certain amyloid-beta (Aβ) proteins that are a likely cause of AD in the human brain. We are using the most advanced imaging technology to answer these questions in patients in order to accelerate drug development and improve patient outcomes.

The central aim of this project is to accelerate research into potential Alzheimer's treatments targeting the brain microvasculature. This will be done through our EyeOnALZ project, which uses Citizen Science (a form of crowdsourcing). Without this crowdsourced program, the same research would otherwise take decades to complete.  Our approach is to transform a time-consuming laboratory task into an online game that anyone can play. Project success depends upon recruiting and sustaining an active population of public volunteers and improving our ability to extract research value from each participant.  We also hope this project provides a hands-on way for people affected by Alzheimer's disease (AD) to make an impact on their own future or that of a loved one, and that it educates the general public about the disease.

In patients with Alzheimer's disease (AD) and dementia, the blood vessels of the brain become leaky, which worsens symptoms like memory loss. We are trying to identify why these blood vessels become leaky. If we understand the cause of this leakage, we can potentially target it with new drugs to improve patient outcomes. 

A major driver of Alzheimer’s disease (AD) is the accumulation of the protein tau that travels through the human brain in a constant pattern. Tau molecules become misshapen and aggregate in AD, though no one has yet identified how, or even if, these tau accumulations result in neuronal death. In this research, we have developed a fluorescent tool that will allow us to watch tau collect in neurons both in cell culture as well as the living adult mouse brain. Using this tool, this research aims to observe directly, in real time, what happens once a neuron develops a tau aggregate, as well as to study which genes increase or decrease in a neuron once it develops one of these tau accumulations. Together, these data will help us better understand the immediate changes that occur in adult neurons when they develop AD-like tau accumulations and may help identify new druggable pathways involved in the development of AD in human patients.

Note: This grant was terminated by the investigator in February of 2018 when she left Harvard University for an industry position.