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Principal Investigator: Colin K Combs
Organization: WEST VIRGINIA UNIVERSITY
Fiscal Year: 2024
Award: $598,003
Funding agency: National Institute on Aging
ABSTRACT: There are significant differences between men and women in the incidence and severity of late-
onset Alzheimer’s Disease (LOAD). After menopause, women are more likely to develop LOAD, and symptoms
of the disease including cognitive impairment are more severe. These symptoms are exacerbated by high
cholesterol which, at midlife, is a major risk factor for LOAD. There is a substantial gap in our knowledge of how
estrogen and cholesterol interact. We propose to examine the role of estrogen and cholesterol in LOAD sex
differences by studying male and female cholesterol-fed rabbits – an unconventional but promising model of
LOAD. These rabbits show significant sex differences in AD-like pathology, estrogen receptor transcriptional
activity and protein expression, and differences in cognition. Cholesterol-fed female rabbits develop beta
amyloid (Aβ) deposits more slowly than cholesterol-fed males and eliminating peripheral estrogen by
ovariectomy more than doubles Aβ levels, suggesting a protective role for estrogen. We have evidence that a
cholesterol diet alters estrogen receptors, significantly increases serum and hippocampal levels of the
cholesterol metabolite, 27-hydroxycholesterol (27-OHC), and female cholesterol-fed rabbits remember
hippocampally-dependent learning better than cholesterol-fed males. 27-OHC is a well-documented
endogenous selective estrogen receptor modulator that may play a role in learning and memory because patients
with mild cognitive impairment (MCI) and AD show elevated 27-OHC levels and we have evidence that
cholesterol-fed rabbits have elevated 27-OHC and memory deficits. We also have data showing there are sex
differences in the transcriptional activity of estrogen receptors and expression of proteins in the presynaptic
active zone and postsynaptic density that are higher in female cholesterol-fed rabbits than in males. Our
research focus on cholesterol-induced increases in 27-OHC has direct clinical relevance because midlife
hypercholesterolemia is a significant risk factor for LOAD and, as noted, 27-OHC is elevated in MCI and LOAD.
In three specific aims, we will manipulate estrogen (Aim 1), 27-OHC (Aim 2), and estrogen receptors (Aim 3) in
cholesterol-fed rabbits to test the hypothesis that sex differences in AD-like cognitive impairment and pathology
are a function of estrogen and can be rescued with estrogen receptor modulation. Using behavioral,
electrophysiological, histochemical, and molecular biological techniques, we will determine the mechanisms by
which estrogen receptor modulation affects memory, neural function, markers of cholesterol and Aβ processing,
and Aβ and tau levels in intact and castrated male and in intact and ovariectomized female cholesterol-fed
rabbits. Our expertise in and track record of behavioral, histochemical, electrophysiological, and molecular
biological research in cholesterol-fed rabbits makes us a particularly well-suited team to conduct these
experiments, further validate this non-transgenic model of LOAD, and positions us to help understand the impact
of sex differences on the molecular determinants of LOAD risk and responsiveness to treatment.
Terms: <21+ years old><27-hydroxycholesterol><5-cholestene-3 beta,27-diol><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ABCA1><ABCA1 protein><AD dementia><AD model><AD pathology><ATP binding cassette transporter 1><Adult><Adult Human><Affect><Aged 65 and Over><Agonist><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's disease risk><Alzheimer's pathology><Alzheimers Dementia><Amentia><Ammon Horn><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Animals><Arimidex><Aβ><Behavioral><Biological><Blood Serum><Brain Pathology><CMKRL2><CNS plasticity><Chemokine Receptor-Like 2><Cholesterol><Clinical Trials><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cornu Ammonis><Data><Dementia><Deposit><Deposition><Diabetes Mellitus><Diet><Differences between sexes><Differs between sexes><Disease><Disorder><Disturbance in cognition><Domestic Rabbit><ER-BETA><ERalpha><ERbeta><ERα><ERβ><ESR-BETA><ESR1><ESR1 gene><ESR2><ESR2 gene><ESRB><ESTRB><Electrophysiology><Electrophysiology (science)><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor 2><Estrogen Receptor alpha><Estrogen Receptor beta><Estrogen Receptor α><Estrogen Receptor β><Estrogen Receptors><Estrogens><Female><G Protein-Coupled Estrogen Receptor><G Protein-Coupled Receptor 30><GPER><GPER gene><GPR30><Gene Transcription><Genes><Genetic Transcription><HDLDT1><Hippocampus><Hypercholesteremia><Hypertension><Impaired cognition><Incidence><Infusion><Infusion procedures><Knowledge><Late Onset Alzheimer Disease><Learning><MT-bound tau><Male Castration><Measures><Membrane><Memory><Memory Deficit><Memory impairment><Mitochondria><Modeling><Molecular><NR3A1><NR3A2><Nerve Degeneration><Neuron Degeneration><Neuronal Plasticity><Neurophysiology - biologic function><Neurophysiology / Electrophysiology><Non-Rodent Model><Obesity><Oophorectomy><Oryctolagus cuniculus><Ovariectomy><Pathology><Pathway interactions><Patients><Peripheral><Position><Positioning Attribute><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Prefrontal Cortex><Primary Senile Degenerative Dementia><Property><Proteins><RNA Expression><Rabbits><Rabbits Mammals><Research><Risk><Risk Factors><Role><SERMs><Selective Estrogen Receptor Modulators><Serum><Severities><Sex Differences><Sexual differences><Signal Pathway><Symptoms><Synapses><Synaptic><Synaptic plasticity><Techniques><Testing><Therapeutic Estrogen><Transcription><Transgenic Mice><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Woman><a beta peptide><abeta><above age 65><adiposity><adult youth><adulthood><after age 65><after menopause><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><alzheimer model><alzheimer risk><amyloid beta><amyloid-b protein><anastrazole><anastrozole><beta amyloid associated pathology><beta amyloid fibril><beta amyloid pathology><biologic><biological research><central nervous system plasticity><cholest-5-ene-3 beta,27-diol><cholesterol-efflux regulatory protein><clinical relevance><clinically relevant><cognitive dysfunction><cognitive loss><cognitive performance><corpulence><density><diabetes><dietary><diets><electrophysiological><experiment><experimental research><experimental study><experiments><female gonadectomy><following menopause><high blood cholesterol><high blood pressure><hippocampal><human old age (65+)><hypercholesterolemia><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><improved><indexing><infusions><inhibitor><late onset alzheimer><male><member><membrane structure><memory dysfunction><men><microtubule bound tau><microtubule-bound tau><mid life><mid-life><middle age><middle aged><midlife><mild cognitive disorder><mild cognitive impairment><mitochondrial><mouse model><murine model><neural degeneration><neural function><neural plasticity><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><neuroplastic><neuroplasticity><neuroprotection><neuroprotective><old age><over 65 years><past menopause><pathway><post-menopausal><postmenopausal><postmenopausal status><postsynaptic><postsynaptic density protein><presynaptic><primary degenerative dementia><programs><protein expression><senile dementia of the Alzheimer type><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><social role><soluble amyloid precursor protein><synapse><tau><tau Proteins><tau factor><young adult><young adulthood><β-amyloid pathology><τ Proteins><≥65 years>