As we get older, our mental functions get less flexible and our memory declines. While our mind can adapt to simple lapses in function, memory loss is generally progressive and can eventually interfere with daily life. Alzheimer’s disease is the most common cause of dementia that involves the abnormal buildup of misfolded protein “plaques” in the brain. Despite significant research efforts aimed at Alzheimer’s therapies, there are currently no cures and very few treatment options. There is an urgent need for creative approaches to identify new targets for therapeutic intervention.
My lab is interested in understanding how biological sex contributes to Alzheimer’s disease. While women experience Alzheimer’s more often and more severely, men diagnosed with Alzheimer’s progress more quickly to death. By identifying the genetic and hormonal differences between men and women with Alzheimer’s, we hope to discover new sex-informed targets to prevent and reverse the disease.
Microglia, the brain’s resident macrophages, have emerged as a key cell type in Alzheimer’s disease. Male and female microglia display divergent responses to AD, which include distinct morphology, phagocytic capacity, cell surface marker expression, and response to inflammatory stimuli. Microgliosis is a pathological hallmark of AD characterized by microglia diversification into a variety of phenotypic states (both protective and destructive). We hypothesize that sex-chromosomally and hormonally driven processes contribute mechanistically to the sex differential microglial response to AD. Our goal is to identify novel pathways that confer risk or resilience for AD to inform therapeutic development.
In addition to determining sex, sex chromosomes play important roles in programming sex-specific features across body systems. Due to the sex chromosome imbalance between males (XY) and females (XX), epigenetic dosage compensation mechanisms, such as X-chromosome inactivation, have evolved. Sex chromosomal mechanisms, such as X-chromosome inactivation and mosaic loss-of-Y have been implicated in AD. We will use multi-omic single cell techniques coupled with disease models to identify how sex chromosomes impact AD progression.
In terms of sex hormones, we are interested in how estrogen signaling through microglia may contribute to the sex differences seen in neuroinflammation with aging and AD. We will use menopausal models, transgenic deletion of estrogen receptors, and estrogen replacement therapies to test the effect of estrogen signaling modulation on microglial phenotypic responses to aging and disease.
B.S., State University of New York College at Geneseo, Geneseo, NY, 2010
M.S., University of Texas at Brownsville, Brownsville, TX, 2015
Ph.D., University of Oklahoma Health Sciences Center, 2022
Honors and Awards
NIH Director’s Early Independence Award, 2022
Provost’s Award for Outstanding Research, OUHSC, 2022
Graduate College Dean Award for Outstanding Research, OUHSC, 2021
Graduate Student Paper of the Year, OUHSC, 2020
Federation of American Societies for Experimental Biology Science Policy Committee, 2023-present
International Society to Advance Alzheimer’s Research and Treatment, 2022-present
Society for Neuroscience, 2021-present
American Aging Association, 2019-present
Joined OMRF scientific staff in 2022
Ocañas SR, Pham KD, Cox JEJ, Keck AW, Ko S, Ampadu FA, Porter HL, Ansere VA, Kulpa A, Kellogg CM, Machalinski AH, Thomas MA, Wright Z, Chucair-Elliott AJ, Freeman WM. Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer's disease. J Neuroinflammation 20:188, 2023 August, PMID: 37587511, PMCID: PMC10433617
Kellogg CM, Pham K, Machalinski AH, Porter HL, Blankenship HE, Tooley KB, Stout MB, Rice HC, Sharpe AL, Beckstead MJ, Chucair-Elliott AJ, Ocañas SR, Freeman WM. Correction to: Microglial MHC‑I induction with aging and Alzheimer's is conserved in mouse models and humans. Geroscience, 2023 August, PMID: 37556087
Ocañas SR, Pham KD, Cox JEJ, Keck AW, Ko S, Ampadu FA, Porter HL, Ansere VA, Kulpa A, Kellogg CM, Machalinski AH, Chucair-Elliott AJ, Freeman WM. Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer's disease. bioRxiv, 2023 June, PMID: 36945656, PMCID: PMC10028852
Ocañas SR, Ansere VA, Tooley KB, Hadad N, Chucair-Elliott AJ, Stanford DR, Rice S, Wronowski B, Pham KD, Hoffman J, Austad S, Stout MB, Freeman WM. Differential regulation of mouse hippocampal gene expression sex differences by chromosomal content and gonadal sex. Molecular Neurobiology. 2022 Aug;59(8):4669-4702. Epub 2022 May 20. PMID: 35589920. PMCID: PMC9119800.
Ocañas SR, Pham KD, Blankenship HE, Machalinski AH, Chucair-Elliott AJ, Freeman WM. Minimizing the ex vivo confounds of cell-isolation techniques on transcriptomic and translatomic profiles of purified microglia. eNeuro. 2022 Mar 28;9(2):ENEURO.0348-21.2022. Print 2022 Mar-Apr. PMID: 35228310. PMCID: PMC8970438.
Bodas M, Subramaniyan B, Moore AR, Metcalf JP, Ocañas SR, Freeman WM, Georgescu C, Wren JD, Walters MS. The NOTCH3 Downstream Target HEYL Regulates Human Airway Epithelial Club Cell Differentiation. Cells. 2021 Nov 18;10(11):3215. PMID: 34831437; PMCID: PMC8620267.
Ansere VA, Ali-Mondal S, Sathiaseelan R, Garcia DN, Isola JVV, Henseb JD, Saccon TD, Ocañas SR, Tooley KB, Stout MB, Schneider A, Freeman WM. Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion. Mech Ageing Dev. 2021 Mar;194:111425. Epub 2020 Dec 28. PMID: 33383072; PMCID: PMC8279026.
Howell RD, Dominguez-Lopez S, Ocañas SR, Freeman WM, Beckstead MJ. Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters. Neurobiol Aging. 2020 Nov;95:195-204. Epub 2020 Aug 3. PMID: 32846275; PMCID: PMC7606778.
Chucair-Elliott AJ*, Ocañas SR*, Stanford DR, Ansere VA, Buettner KB, Porter H, Eliason NL, Reid JJ, Sharpe AL, Stout MB, Beckstead MJ, Miller BF, Richardson A, Freeman WM. Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia. Commun Biol. 2020 Nov 19;3(1):693. PMID: 33214681; PMCID: PMC7678837.