PROJECT SUMMARY We and others have shown that blocking FSH action either pharmacologically or genetically prevents both osteoporosis and obesity [e.g. Cell, 2006, PMID: 16630814; Nature, 2017, PMID: 28538730]1-7. More recently, we reported that FSH also acts on hippocampal neurons to trigger neurodegeneration in Alzheimer's disease (AD) mice, and that blocking FSH action prevents the onset of AD–like features [Nature, 2022, PMID: 35236988]8. Towards intercepting FSH actions on bone, body fat and brain, we recently developed a therapeutic FSH–blocking antibody––MS-Hu6––that acts by binding to a 13–amino–acid–long epitope on FSHβ to prevent its access to the FSH receptor (FSHR)9. Towards its future use in people, MS-Hu6 has undergone early–stage testing. We find that it has a high affinity for FSH (KD=7,52 nM), displays a β phase t1/2 of 7.5 days, distributes to bone, fat and brain, is safe when injected into monkeys, and is thermostable [PNAS, 2020, PMD: 33127753; eLife, 2022, PMID: 36125123]2,9. The NIA–sponsored SWAN Study teaches us that, during the menopausal transition, when serum FSH rises in the face of unperturbed estrogen, there is a sharp reduction in bone mass, onset of visceral adiposity, and spikes in cognitive decline10-12. We believe that MS-Hu6 could potentially be used to prevent three diseases of public health magnitude—all at once––within this FSH–high/estrogen–replete window. A broader question, however, arises whether, in addition to preventing their onset, can MS-Hu6 be purposed for treating established osteoporosis, obesity and AD—the armamentarium of therapies for which pales in comparison to that for diabetes, hypertension or cancer. Contemporaneously reproduced in the Rosen lab, we find that MS-Hu6 does stimulate new bone formation, and, in doing so, reverses lost bone in young mice. We hypothesize that MS-Hu6 will not only prevent, but also cure established osteoporosis, obesity and AD in aged mice. For this, we will use a two–pronged approach for blocking FSH action: pharmacologic by MS-Hu6 and/or genetic by abrogating the Fshr conditionally in 18–month–old mice. Specific Aim 1 will study the effects of this strategy by comprehensively phenotyping skeletons of old gonadectomized male and female mice following FSH blockade. In Specific Aim 2, we will induce obesity in old mice and administer MS-Hu6 or delete FSHRs globally, followed by detailed body composition and metabolic studies, with the expectation of achieving a lean, thermogenic phenotype. For Specific Aim 3, we will age APP-KI mice, which harbor human APP substitutions, and begin injecting MS-Hu6 once deficits in cued and recognition memory set in—followed by detailed neurophenotyping. Together, these studies should not only allow us to understand how aging bone, fat tissue and brain respond to FSH perturbations, but also provide proof–of–concept for future clinical studies. These experiments will be performed on our Good Laboratory Practice (GLP) Platform [per...