A humanized monoclonal FSH antibody for Alzheimer's Disease and co-occurring health conditions in Down Syndrome

Project Summary/Abstract People with Down Syndrome have many co-occurring health conditions, but one of the most common is Alzheimer’s Disease. People with Down Syndrome begin to accumulate Alzheimer’s pathology at much earlier ages than people without Down Syndrome. Accordingly, by the age of 60, almost all people with DS will be symptomatic for Alzheimer’s Disease dementia, whereas less than 10% of people without Down Syndrome will have Alzheimer’s Disease dementia. Because Alzheimer’s Disease impacts virtually all people with Down Syndrome, developing interventions to block or slow the progression of Alzheimer’s Disease may be especially helpful for increasing the quality of life for people with Down Syndrome. Our previous work showed that elevated levels of follicle-stimulating hormone (FSH) enhance the genesis and progression of Alzheimer’s pathology in mouse models of Alzheimer’s Disease. This led us to wonder whether Down Syndrome might be associated with elevated levels of FSH. Here, we will first measure FSH throughout the lifespan in two mouse models of Down Syndrome and explore possible mechanisms by which FSH might be altered in Down Syndrome. In our published work, we also developed a first-in-class monoclonal antibody targeting FSH; the antibody binds to the FSH receptor thereby preventing FSH from acting on its’ receptor. We will then determine whether administration of this antibody late in the lifespan reduces age-related accumulation of Alzheimer’s-like pathology in mouse models of Down Syndrome, as well as cognitive function. Lastly, we will compare antibody administration in young and aged mice with Down Syndrome and examine the impact on metabolic and non-metabolic conditions that are highly prevalent in Down Syndrome and arise from FSH- sensitive organs. The overarching goal of our proposed work is to determine if and when FSH is elevated in Down Syndrome, and probe whether reducing the actions of FSH helps normalize physiological function, thereby unmasking a new therapeutic target for the treatment of multiple co-occurring diseases in Down Syndrome.