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Genetic studies have recently uncovered several genes that can elevate the risk of developing Alzheimer’s disease (AD), including the BIN1 gene as the second strongest genetic risk factor for late onset AD. My lab has generated a BIN1 transgenic model to mimic the increase of BIN1 protein in the brains of people with AD. My goal is to use this transgenic mouse model to investigate how BIN1 functions as a risk factor in AD. I expect that my proposed research will significantly advance the knowledge about BIN1's function in the physiology of the brain, and reveal how it contributes to AD pathology.

The incredibly complex circuitry of the brain is the structural foundation of normal cognition. In Alzheimer’s disease (AD), these neural circuits begin to break down, leading to the hallmark cognitive decline of AD. This happens at many sites throughout the brain over many years, yet remains invisible to clinical imaging techniques like MRI until so advanced that it is likely irreversible. Our goal is to develop new MRI approaches that can reveal these microscopic circuit injuries in model systems and in patients suffering from AD. With such a technique in-hand, we will be far better positioned to understand and ultimately disrupt the pathways that lead to neural circuit injury in AD.

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. 

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. 

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.

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.

Beta-amyloid (Aβ) protein accumulates abnormally in the Alzheimer’s brain, to a degree that is believed to be sufficient to induce neuronal cell death. Evidence suggests that the levels and distribution of lipids in the brain influence the transport and deposition of Aβ protein. The aim of this proposal is to determine the effect of a new treatment based on the administration of a natural modified protein that is able to mobilize lipids in a transgenic mouse model of AD. This protein, the ApoA-I-Milano variant, has been shown to be protective in cardiovascular diseases; however, its properties have never been tested in brain diseases.

The brain is a complicated system whose different parts interact to support a variety of cognitive functions. This complexity makes it difficult to treat diseases such as Alzheimer’s and Parkinson’s, where many different brain areas can be affected, but lead to very similar deficits, such as memory dysfunction. Our research provides a framework of tools to “reconstruct” the brain and build models of different dementias to characterize the unique features of each disease and the final common paths to cognitive impairment. As our work progresses, it will be used to evaluate the potential of therapeutic interventions to help identify treatment targets, or areas of the brain that, if treated, are most likely to result in the best outcome for the individual.

Alzheimer's disease (AD) is the most common cause of dementia and the sixth leading cause of death in the United States. It is critical that we find new therapies to prevent and treat AD. The experiments in this proposal are designed to find new pathways by which toxic forms of beta amyloid (Aβ), a peptide associated with AD, damages microtubules, tube-like structures used to move components around in cells, including neurons in the brain. Typically, damage to microtubules is blamed on abnormal tau formations in the Alzheimer’s brain, but we plan to test the novel hypothesis that Aβ has neurodegenerative effects independent of tau that affect microtubule stability, and that microtubule stabilizing agents can protect neurons against Aβ neurotoxicity. New drugs will be tested to determine if they can reverse some of the detrimental effects of Aβ accumulation in the brain.

Diet plays an important role in the development of many chronic diseases. However, we still don’t have a good understanding of which dietary components are most important for the prevention of Alzheimer’s disease (AD). In this project, we will identify key healthy dietary patterns that can form the foundation of dietary recommendations to lower Alzheimer’s risk. This is important because diet is among the risk factors that are modifiable; thus we can change our behavior and lower our risk of this devastating disease.