2024 Alzheimer's Association Research Grant (AARG)
Unraveling the Therapeutic Potential of SPPL2b in Alzheimer's Disease
Can inhibiting a protein linked to brain inflammation lower beta-amyloid levels and promote brain health in people with Alzheimer’s?
Simone Tambaro, Ph.D.
Karolinska Institutet
Stockholm, Sweden
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.
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.
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.