Simone Tambaro

The main question that we want to answer in this project is, how does the brain-specific intramembrane enzyme SPPL2b affect Alzheimer's disease (AD), and may it be used as a target for the creation of novel therapies? AD is characterized by an abnormal accumulation of toxic proteins (amyloid peptides) in the brain, inflammation, and progressive memory loss that affect a person’s ability to carry out daily activities. Recently, immunotherapy showed positive results in reducing plaque and slowing down cognitive decline. Still, this therapeutic approach cannot block the progression of AD and reverse memory impairment highlighting the important need in finding novel approaches to treat this disease. Our study focuses on the SPPL2b enzyme, which is involved in processing proteins involved in amyloid peptide production, inflammation, and memory process. We think that the modulation or inhibition of SPPL2b activity may help prevent the synthesis of dangerous proteins and lessen brain inflammation. We will investigate this theory by looking at the SPPL2b gene deletion results in a mouse model of AD. Additionally, we will look for SPPL2b and associated proteins in samples of human brains from various disease stages. This will enable us to comprehend the relationship between SPPL2b and AD. Additionally, we will conduct lab tests and computer simulations to look for potential SPPL2b-specific inhibitors. Our goals are to understand how SPPL2b contributes to Alzheimer's, find potential new ways to detect the disease early, and identify compounds that can block the enzyme's harmful actions. If successful, this research could lead to new drugs that slow down or halt the progression of Alzheimer's disease.

Background The protein fragment beta-amyloid has long been studied as a key brain molecule in Alzheimer’s. Beta-amyloid tends to accumulate into clumps called plaques, which may hinder nerve cell communication in the brain and lead to cognitive (brain function) decline and brain cell death. Beta-amyloid is produced from a larger molecule, amyloid precursor protein (APP), in a two-stage “cutting” process involving proteins called secretases. Many research teams have searched for ways to hinder this cutting process in order to reduce amyloid levels and improve cognitive health in people with Alzheimer’s. <br /> <br /> A team, led by Dr. Simone Tambaro, has been examining the role of a protein called SPPL2b, which helps produce other proteins linked to the immune system. SPPL2b also cuts a protein known as BRI2, which has been shown to prevent the making of beta-amyloid from APP. In preliminary studies with mouse nerve cells, the researchers found that by reducing SPPL2b activity, they could promote the ability of BRI2 to hinder beta-amyloid production in the cells. Research Plan Dr. Tambaro and the team will now conduct a larger study to explore the relationship between SPPL2b and beta-amyloid in Alzheimer’s. For this effort, they will use a novel Alzheimer’s-like mouse model that expresses APP. They will also use brain tissue from people who had Alzheimer’s disease, as well as samples of blood and cerebrospinal fluid (CSF, the biological fluid surrounding the brain and spinal cord) from people with Alzheimer’s. Studies show that protein changes in the blood and CSF can affect dementia-related changes in the brain. <br /> <br /> First, the researchers will inhibit SPPL2b in their mice and assess how this treatment may impact amyloid levels, inflammation, brain cell activity and memory in the animals. Next, they will measure SPPL2b levels in the brain, blood, and CSF of people with Alzheimer’s. They will also assess how the shape and function of this protein may become altered in the disease. Lastly, Dr. Tambaro’s team will use an advanced scientific technique called machine learning, a form of artificial intelligence, to more thoroughly analyze SPPL2b’s molecular structure. This work will clarify how the protein is shaped, and it may identify certain parts of the protein that can be targeted by drug compounds. Impact Results from Dr. Tambaro’s study will shed new light on how beta-amyloid accumulation takes place in Alzheimer’s. They may also lead to novel dementia therapies that target SPPL2b.