Project Details

Description

PROJECT SUMMARY Alzheimer’s disease (AD) stands out as notable in two respects––in not having a cure and in affecting women more than men. While declining estrogen has been thought to underpin post–menopausal AD, there is a clear clinical correlation of AD with rising levels of follicle–stimulating hormone (FSH). Most notably, there is a ‘spike’ in cognitive decline in women in the early years of the menopausal transition, when serum estrogen is normal and FSH levels begin to rise. Collaborative studies between the Mount Sinai and Emory groups have identified FSH as a potential driver for AD—and suggest that rising FSH levels may contribute to the disproportionate increase of AD in aging women. Notably, we find that FSH receptors (FSHRs) are expressed in both mouse and human brain, and that the injection of recombinant FSH or ovariectomy (that elevates serum FSH) aggravates AD pathology and cognitive decline in 3xTg mice. Inhibiting the action of FSH in 3xTg or APP/PS1 mice by an FSH–blocking antibody or downregulating Fshr expression in the hippocampus prevents onset of the AD phenotype. The Emory group also provides strong preliminary evidence that FSH upregulates C/EBPβ, which activates asparagine endopeptidase (AEP), a δ–secretase that cleaves amyloid precursor protein (APP) and Tau––resulting in neuritic plaques and neurofibrillary tangles, respectively. The goal of the transdisciplinary collaboration between the disciplines of endocrinology and neuroscience is to fully understand the mechanism of FSH action on AD–vulnerable brain regions. Thus, in Specific Aim 1, we will map the distribution and cellular localization of the FSHR and its signaling partners CEBPB and LGMN in human and mouse brain using single–transcript technologies. In Specific Aim 2, we will examine the function of the brain FSHR in driving AD pathology and cognitive decline. For this, we will downregulate or overexpress the Fshr in specific brain areas of 3xTg mice by stereotaxically injecting AAV expressing siFshr or Fshr. We will also study the effect of high FSH in 3xTg mice rendered haploinsufficient in Cebpb, and delineate the transcriptomic architecture of FSH–treated human neuronal cells by RNA–seq. In Specific Aim 3, we will determine whether deleting the Fshr or inhibiting FSH action by our murine FSH blocking antibody, Hf2, injected over the lifespan of 3xTg mice can prevent the onset of cognitive decline. To contemporaneously replicate our data, the Emory group will study the effect of treating established cognitive impairment with Hf2 in 18–month–old APP knock–in (KI) mice. In all, our proof–of–concept studies––conducted using our Good Laboratory Practices (GLP) Platform––should not only establish a role for high FSH in driving AD, but also provide a framework for the future testing of our humanized FSH–blocking antibody, Hu6, in aging women.
StatusActive
Effective start/end date30/09/2131/08/23

Funding

  • National Institute on Aging: $1,267,500.00
  • National Institute on Aging: $1,268,438.00

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