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Principal Investigator: VAHRAM HAROUTUNIAN
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2022
Award: $1,267,500
Funding agency: National Institute on Aging
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.
Terms: <3xTg><3xTg-AD mice><3xTg-AD mouse><AD dementia><AD model><AD pathology><AKT><Affect><Aging><Akt protein><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer like pathology><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimer's disease like pathology><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's disease therapeutic><Alzheimer's pathology><Alzheimer's therapeutic><Alzheimers Dementia><Alzheimers disease><Amentia><Ammon Horn><Amyloid A4 Protein Precursor><Amyloid Plaques><Amyloid Protein Precursor><Amyloid beta-Protein Precursor><Amyloid β-Protein Precursor><Antibodies><Architecture><Area><Asparagine><Automobile Driving><Blocking Antibodies><Blood><Blood Reticuloendothelial System><Blood Serum><Body fat><Brain><Brain Nervous System><Brain region><Bypass><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cholesterol><Clinical><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complement><Complement Proteins><Cornu Ammonis><Coupled><Data><Dementia><Differences between sexes><Differs between sexes><Discipline><Disease><Disorder><Disturbance in cognition><Encephalon><Endocrine Gland Secretion><Endocrinology><Endopeptidases><Energy Expenditure><Energy Metabolism><Engineering / Architecture><Estrogen Replacements><Estrogens><Evaluation><Evolution><FSH Receptors><Fats><Fatty acid glycerol esters><Female><Follicle Stimulating Hormone><Follicle Stimulating Hormone Receptor><Follitropin><Future><Genetic study><Goals><Gonadal structure><Health Hazards><Hippocampus><Hippocampus (Brain)><Histocytochemistry><Hormones><Human><Hypercholesteremia><Impaired cognition><Injections><Intracellular Communication and Signaling><KI mice><Knock-in Mouse><L-Asparagine><Length of Life><Life><Longevity><MT-bound tau><Maps><Medical><Menopause><Metabolism and Endocrinology><Mice><Mice Mammals><Modern Man><Murine><Mus><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocyte><Neurofibrillary Tangles><Neurons><Neurosciences><Obesity><Oophorectomy><Organ><Osteoporosis><Ovariectomy><Pathogenesis><Pathway interactions><Peptide Peptidohydrolases><Phase><Phenotype><Physiology><Pituitary Hormones><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Primary Senile Degenerative Dementia><Protein Kinase B><Proto-Oncogene Proteins c-akt><Public Health><RAC-PK protein><RNA Seq><RNA sequencing><RNAseq><Recombinant Follicle Stimulating Hormone><Recombinant TSH><Recombinant Thyroid-Stimulating Hormone><Rodent><Rodentia><Rodents Mammals><Role><Senile Plaques><Serum><Sex Differences><Sexual differences><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Specific qualifier value><Specified><Symptoms><Technology><Testing><Textbooks><Therapeutic Estrogen><Therapeutic FSH><Therapeutic Hormone><Thyreotropin><Thyroid><Thyroid Gland><Thyroid Head and Neck><Thyroid Stimulating Hormone><Thyroid-Stimulating Hormone><Thyrotropin><Transcript><Treatment Protocols><Treatment Regimen><Treatment Schedule><Up-Regulation><Upregulation><Woman><abeta accumulation><abeta aggregation><adiposity><aged><alzheimer model><amyloid beta accumulation><amyloid beta aggregation><amyloid beta plaque><amyloid precursor protein><amyloid β accumulation><amyloid β aggregation><amyloid-b plaque><aβ accumulation><aβ aggregation><aβ plaques><base><biological signal transduction><bone><bone cell><bone loss><brain tissue><c-akt protein><cognitive dysfunction><cognitive function><cognitive loss><cored plaque><corpulence><dementia of the Alzheimer type><design><designing><diffuse plaque><disease phenotype><driving><endopeptidase A><energy balance><female gonadectomy><gonad><gonads><good laboratory practice><high blood cholesterol><hippocampal><histochemistry><histochemistry/cytochemistry><hormonal signals><hormone signals><hypercholesterolemia><interdisciplinary collaboration><knock-down><knockdown><knockin mice><laser capture microdissection><life span><lifespan><loss of function><male><men><men's><microtubule bound tau><microtubule-bound tau><mild cognitive disorder><mild cognitive impairment><mouse model><murine model><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuronal><overexpress><overexpression><pathway><polyclonal antibody><post-menopausal><postmenopausal><prevent><preventing><primary degenerative dementia><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><receptor expression><related to A and C-protein><secretase><senile dementia of the Alzheimer type><sex-dependent differences><sex-related differences><sex-specific differences><shRNA><short hairpin RNA><siRNA><small hairpin RNA><social role><tangle><tau><tau Proteins><tau factor><transcriptome sequencing><transcriptomics><transdisciplinary collaboration><τ Proteins>