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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.

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).

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.

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. 

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.

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.

Atherosclerosis, or hardening of the arteries, is increasingly recognized as an important risk factor for dementia. Yet, it remains unclear whether the progression of atherosclerosis at different locations in the arterial system also contributes to changes in the structure or function of the brain, and ultimately to dementia. Knowledge of the dynamics of atherosclerosis and its role in brain changes will greatly improve our insight into the development of dementia. At a later point, this knowledge may even offer therapeutic or preventive opportunities to reduce the number of persons suffering from dementia by targeting atherosclerosis.

For screening and clinical management, and for clinical trials, it would be extremely useful to be able to monitor the pathological progression of Alzheimer’s disease (AD), especially during the decades preceding the onset of clinical symptoms when AD spreads silently in the brain. To date, postmortem examination remains the only tool to confirm and stage AD diagnosis. We found that a tiny brainstem nucleus, the locus ceruleus (LC), is especially vulnerable and earliest-damaged in AD. Furthermore, investigating postmortem tissue, we found evidence that in AD patients, the LC showed linear and progressive shrinkage. We will develop a histologically-validated clinical MRI [magnetic resonance imaging] template for detecting LC shrinkage. This should allow us to track AD progression on a case-by-case in individuals and permit intervention before a substantial amount of neurons have died. LC volumetry is potentially more scalable and economical than other potential AD biomarkers, and could be developed for longitudinal screening. Having such a method in place would in turn make it more feasible to identify and triage high-risk candidates for less accessible, more expensive, and more invasive studies, including PET [positron emission tomography] scans and spinal taps.

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.