The Yin Lab

LABORATORY OF NEUROMETABOLISM AND NEUROINFLAMMATION

The Yin Laboratory at the University of Arizona is dedicated to advancing the understanding of the molecular and cellular mechanisms of neurodegeneration and the development of novel therapeutics against neurodegenerative diseases. A major focus of our research is on the role of lipid metabolism in Alzheimer’s disease (AD) and its mechanistic interactions with mitochondrial dysfunction, neuroinflammation and major AD risk factors such as the APOE4 gene and the female sex. Built upon our recent findings, we propose a lipid-centric AD cascade that bridges the amyloid hypothesis, the mitochondrial hypothesis, and the APOE4 hypothesis of AD by their convergence at lipid metabolism. We are now actively developing novel disease-modifying AD therapeutics by restoring lipid homeostasis in the degenerating brain. Moreover, we are also interested in the role of the maternally inherited mitochondrial genome (mtDNA) in metabolically reprogramming the brain and modifying AD risks.

Our Research

Disrupted lipid degradation in Alzheimer’s disease:

Abundant clinical evidence has demonstrated disrupted lipid homeostasis –including the accumulation of lipid droplets– in different stages of AD. However, the precise mechanisms by which lipid dyshomeostasis initiates and subsequently promotes AD pathologies, remain elusive. We focus on the degradation / catabolism of the essential building blocks of lipids – fatty acids (FA), a process that predominantly occurs in astrocytes. Our recent work has revealed that loss of FA degradation by astrocytic mitochondria is sufficient to induce lipid droplet accumulation and reactive astrogliosis followed by progressive and human AD-resembling neuroinflammation and neurodegeneration. Further, we show that amyloidosis metabolically reprograms astrocytes towards diminished FA degradation and increased LD accumulation (Mi et al., Nat Metab, 2023). Now, we are determining the mechanism by which early amyloid pathology metabolically reprograms astrocytes towards AD-associated transformations, and how impaired astrocytic FA degradation drives or exacerbates AD-related amyloid and tau pathologies. Translationally, we are also exploring the therapeutic potential ofpromoting lipid degradation pathways in astrocytes against AD and other lipid-implicated neurodegenerative diseases.

APOE4 regulation of neuron-astrocyte metabolic coupling:

Apolipoprotein E (APOE) is a lipid-binding protein, and its ε4 variant (APOE4) is the strongest genetic risk factor for the predominant, sporadic form of AD. Our research explores how APOE4 disrupts brain lipid metabolism and how such disruption induces brain phenotypic shift and increases AD risk. Our work has revealed a loss-of-function role of APOE4 in eliminating excessive and/or detrimental lipidsfrom the brain. This disruption –involving both neurons and astrocytes–consequently leads to bioenergetic deficit and lipid dyshomeostasis. Furthermore, we show that diminished capability of APOE4 astrocytes in removing lipids accounts for their compromised support to neurons (Qi et al., Cell Rep, 2021). Currently, our research focuses on elucidating APOE4-induced metabolic shift across brain cell types during aging, and how such a shift triggers functional changes in inflammatory responses in APOE4 brains.

Perimenopause in brain aging and Alzheimer’s disease:

Perimenopause, unique to females, is neurologically a critical transition state characterized by bioenergetic and neuroinflammatory changes that are reminiscent of prodromal AD (Yin et al., Neurobio Aging, 2015). Despite the strong interaction between APOE4 and female sex, the mechanisms by which these risk factors converge to disrupt neural functions remain to be explored. Our goal is to identify the mechanisms, at the cellular level, by which brain- and systemic metabolic transformations modulate neuroimmune systems in the female aging brain and their interactions. We are currently investigating the unique role of glial cells in modulating the neuroimmune systems during perimenopause and its interaction with the APOE4 allele. To date, we have shown that perimenopausal transition and APOE4 synergistically contribute to neuroimmune endophenotypes that predispose APOE4-carrying postmenopausal women to a substantially higher AD risk.

Mitochondrial genome and Alzheimer’s disease:

Maternal –but not paternal– inheritance is associated with increased AD risk, indicating an important role of the maternally inherited mitochondrial genome (mtDNA). mtDNA haplotype variation modifies not only metabolic and functional phenotypes at both cellular and system levels, but also AD risks. We are studying how mtDNA variance and instability alter the metabolic profiles of different cell types in the AD brains.

Funding Sources

Meet Our Team

Fei Yin, PhD

Associate Professor

Principle Investigator

Email: feiyin@arizona.edu

Phone: 520-626-4102

Office: BSRL 471

More Details

Current Positions

Associate Professor with tenure, Department of Pharmacology, College of Medicine Tucson

Assistant Director for Translational Neuroscience, Center for Innovation in Brain Science, UAHS

Associate Professor, Graduate Interdisciplinary Program in Neuroscience

Associate Professor, Clinical Translational Sciences, UAHS

Education

• Ph.D., Pharmaceutical Sciences, University of Southern California, Los Angeles, CA; Advisor: Enrique Cadenas, M.D., Ph.D.

• M.S., Computer Science, University of Southern California, Los Angeles, CA.

• M.S., Regulatory Science, University of Southern California, Los Angeles, CA

• B.S., Biochemistry, Nanjing University, Nanjing, China

Research Expertise

Mitochondrial Biology; Alzheimer’s Disease; Lipid Metabolism; Neuroinflammation; Glial Cells; Female Reproductive Aging.

Teaching

• Course Director, PHCL 553 – Neuropharmacology

• Instructor, PHCL 551A – Molecular Targets of Pharmacological Agents

• Instructor, CTS 641A – Problem Based Translational Research in Alzheimer’s Disease and Related Dementias I

• Instructor, PHCL 555 – Cancer Therapeutics

• Core Faculty, Translational Research in Alzheimer’s Disease and related Dementias (TRADD) Training Program (NIH T32AG082631)

Guoyuan Qi, Phd

Principle Research Specialist

Research Interest: The cell type-specific impact of ApoE4 on brain bioenergetics

Yashi Mi, phd

Principle Research Specialist

Research Interest: The role of astrocytic fatty acid degradation in regulating brain lipid homeostasis

Huajun Pan

PHD Student, Medical Pharmacology

Research Interest: lipid metabolism in mediating ApoE4 disruption of astrocytic inflammatory response

Hobbies: Baking, Tennis

Kyle Jenkins

PHD Student, Medical Pharmacology

Research Interest: bioinformatics, multi-omics analysis

Hobbies: Martial Arts, Drawing

Publications

*corresponding author; ^#co-first author.

Garcia-Macia M*, Yin F*. Career Pathways, Part 15. Nat Metab. 2024. https://doi.org/10.1038/s42255-024-01122-8.

Schultheis N, Connell A, Kapral A, Becker RJ, Mueller R, Shah S, O’Donnell M, Roseman M, Swanson L, DeGuara S, Wang W, Yin F, Saini T, Weiss RJ, Selleck SB. Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease. iScience. 2024 Jul 2;27(7):110256.

Mi Y^#, Qi G^#, Vitali F, Shang Y, Raikes AC, Wang T, Jin Y, Brinton RD, Gu H, Yin F*. Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration. Nat Metab. 2023 March; 5(3):445-465.
- Featured by Nature Metabolism News & Views: Rubio-Atonal LF and Ioannou MS. Astrocytic OxPhos: more than just energy production. Nat Metab. 2023 March; 5(3):362-363.

Yin F*. Lipid Metabolism and Alzheimer’s Disease: Clinical Evidence, Mechanistic Link and Therapeutic Promise. FEBS J. 2023 Mar;290(6):1420-1453. (Invited State-of-the-Art Review).

Mishra A, Wang Y, Yin F, Vitali F, Rodgers KE, Soto M, Mosconi L, Wang T, Brinton RD. A tale of two systems: Lessons learned from female mid-life aging with implications for Alzheimer’s prevention & treatment. Ageing Res Rev. 2022 Feb;74:101542.

Qi G, Mi Y, Yin F*. Characterizing Brain Metabolic Function Ex Vivo with Acute Mouse Slice Punches. STAR Protoc. 2021 May 23;2(2):100559.

Ren B, Wang L, Shi L, Jin X, Liu Y, Liu RH, Yin F, Cadenas E, Dai X, Liu Z, Liu X. Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21. Redox Biol. 2021 May;41:101940.

Liu X, Li X, Xia B, Jin X, Zou Q, Zeng Z, Zhao W, Yan S, Li L, Yuan S, Zhao S, Dai X, Yin F, Cadenas E, Liu RH, Zhao B, Hou M, Liu Z, Liu X. High-fiber diet mitigates maternal obesity-induced cognitive and social dysfunction in the offspring via gut-brain axis. Cell Metab. 2021 May 4;33(5):923-938.e6.

Qi G^#, Mi Y^#, Shi X, Gu H, Brinton RD, Yin F*. ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism. Cell Rep. 2021 Jan 5;34(1):108572.

Mi Y, Qi G, Brinton RD, Yin F*. Mitochondria Targeted Therapeutics for Alzheimer’s Disease: The Good. The Bad. The Potential. Antioxid Redox Signal. 2021 Mar 6;34(8):611-630. doi: 10.1089/ars.2020.8070.

Mishra A, Shang Y, Wang Y, Bacon ER, Yin F, Brinton RD. Dynamic Neuroimmune Profile during Mid-life Aging in the Female Brain and Implications for Alzheimer Risk. iScience. 2020 Nov 20;23(12):101829.

Wang Y, Shang Y, Mishra A, Bacon E, Yin F, Brinton RD. Midlife Chronological and Endocrinological Transitions in Brain Metabolism: System Biology Basis for Increased Alzheimer’s Risk in Female Brain. Sci Rep. 2020 May 22;10(1):8528.

Romani A, Yin F, Trentini A, Bonaccorsi G, Cervellati C, Brinton RD. Brain and serum cholesterol dyshomeostasis during the perimenopausal transition: A possible risk factor for Alzheimer’s disease. Gynecological and Reproductive Endocrinology and Metabolism.2020; 1(3):192-201.

Liu Z, Dai X, Zhang H, Shi R, Hui Y, Jin X, Zhang W, Wang L, Wang Q, Wang D, Wang J, Tan X, Ren B, Liu X, Zhao T, Wang J, Pan J, Yuan T, Chu C, Lan L, Yin F, Cadenas E, Shi L, Zhao S, Liu X. Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment. Nat Commun. 2020 Feb 18;11(1):855.

Qi G, Mi Y, Yin F*. Cellular Specificity and Inter-cellular Coordination in the Brain Bioenergetic System: Implications for Aging and Neurodegeneration. Front Physiol. 2020 Jan 8;10:1531.

Wang Y, Hernandez G, Mack WJ, Schneider LS, Yin F, Brinton RD. Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy. Menopause. 2020 Jan;27(1):57-65.

Bacon ER, Mishra A, Wang Y, Desai MK, Yin F, Brinton RD. Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiol Aging. 2019 Feb;74:213-224.

More Publications

Yin F*, Yao J, Brinton RD, Cadenas E. The metabolic-inflammatory axis in brain aging and neurodegeneration. Front Aging Neurosci. 2017 Jun 28;9:209.
Liu Z, Patil IY, Sancheti H, Yin F, Cadenas E. Effects of lipoic acid on high-fat diet-induced alteration of synaptic plasticity and brain glucose metabolism: a PET/CT and ¹³C-NMR study. Sci Rep. 2017 Jul 14;7(1):5391.
Yin F*, Sancheti H, Patil I, Cadenas E. Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radic Biol Med. 2016 May 3. pii: S0891-5849(16)30216-7.
Yin F, Sancheti H, Liu Z, Cadenas E. Mitochondrial function in ageing: Coordination with signaling and transcriptional pathways. J Physiol. 2016 Apr 15;594(8):2025-42.
Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E. Perimenopause as a neurological transition state. Nat Rev Endocrinol. 2015 Jul;11(7):393-405.
Yin F, Yao J, Sancheti H, Feng T, Melcangi RC, Morgan TE, Finch CE, Pike CJ, Mack WJ, Cadenas E, Brinton RD. The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity. Neurobio Aging. 2015 Apr 1. pii: S0197-4580(15)00198-0.
Yin F*, Cadenas E. Mitochondria: the cellular hub of the dynamic coordinated network. Antioxid Redox Signal. 2015 Apr 20;22(12):961-4. (Forum Issue Editorial)
Klosinski LP, Yao J, Yin F, Fontehc AN, Harrington MG, Christensen TA, Trushina E, Brinton RD. White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer’s Disease. EBioMedicine. 2015 Dec; 2(12):1888–1904.
Liu Z, Sancheti H, Cadenas E, Yin F*. The energy-redox axis in mitochondria: interconnection of energy-transducing capacity and redox status. Mitochondria in Liver Disease. 2015. CRC Press (Book Chapter).
Liu Z, Patil IY, Jiang T, Sancheti H, Walsh JP, Stiles BL, Yin F, Cadenas E. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. PLoS One. 2015 May 29;10(5):e0128274.
Yin F, Boveris A, Cadenas E. Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid Redox Signal. 2014 Jan 10;20(2):353-71.
Wu JB, Shao C, Li X, Li Q, Hu P, Shi C, Li Y, Chen YT, Yin F, Liao CP, Stiles BL, Zhau HE, Shih JC, Chung LW. Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. J Clin Invest. 2014 Jul 1;124(7):2891-908.
Agarwal AR, Yin F, Cadenas E. Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells. Am J Respir Cell Mol Biol. 2014 Aug;51(2):284-93.
Li B, Iglesias-Pedraz JM, Chen LY, Yin F, Cadenas E, Reddy S, Comai L. Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. Aging Cell. 2014 Apr;13(2):367-78.
Agarwal AR, Yin F, Cadenas E. Metabolic shift in lung alveolar cell mitochondria following acrolein exposure. Am J Physiol Lung Cell Mol Physiol. 2013 Nov 15;305(10):L764-73.
Yin F, Jiang T, Cadenas, E. Translating the Powerhouse: Redox Signalling: Metabolic triad in brain aging: mitochondria, insulin/IGF1 signaling, and JNK signaling. Biochem Soc Trans. 2013 Feb 1;41(1):101-5.
Jiang T, Yin F, Yao J, Brinton RD, Cadenas E. Lipoic acid restores age-associated impairment of brain energy metabolism through the modulation of Akt/JNK signaling and PGC1α transcriptional pathway. Aging Cell. 2013 Dec;12(6):1021-31.
Sancheti H, Akopian G, Yin F, Brinton RD, Walsh J, Cadenas E. Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer’s disease. PLoS One. 2013 8(7): e69830.
Yin F, Sancheti H, Cadenas E. Mitochondrial thiols in the regulation of cell death pathways. Antioxid Redox Signal. 2012 Dec 15;17(12):1714-27.
Yin F, Sancheti H, Cadenas E. Silencing of nicotinamide nucleotide transhydrogenase impairs cellular redox homeostasis and energy metabolism in PC12 cells. Biochim Biophys Acta 2012 1817: 401-9.
Ermak G, Sojitra S, Yin F, Cadenas E, Cuervo AM, Davies KJ. Chronic Expression of RCAN1-1L protein induces mitochondrial autophagy and metabolic shift from oxidative phosphorylation to glycolysis in neuronal Cells. J Biol Chem 2012 287: 14088-98.
Lam PY, Yin F, Hamilton RT, Boveris A, Cadenas E. Elevated neuronal nitric oxide synthase expression during ageing and mitochondrial energy production. Free Radic Res 2009 43: 431-439.

Join Us

Postdoctoral Scholars:

NIH-funded positions are available for highly motivated postdoctoral researchers with training background and research experience in the areas of neuroscience, molecular and cell biology, pharmacology, bioinformatics, or metabolism. Interested individuals should contact Dr. Yin at feiyin@arizona.edu with their current CV and a summary of research experience and interest.

Graduate Students:

Prospective graduate students can join our lab through multiple UArizona graduate programs.

• Arizona Biological & Biomedical Sciences (ABBS)

• Graduate Interdisciplinary Program (GIDP) in Neuroscience

• Clinical Translational Science (CTS)

• Medical Pharmacology (MedPharm)

Please email Dr. Yin at feiyin@arizona.edu if you are interested in joining our lab or having a rotation through these programs. PhD students in our lab are also eligible to apply for the NIH-funded T32 training grant support.

Undergraduate Students:

Prospective undergraduate students who are motivated and interested in having long-term research experience (~ two years) should contact Dr. Yin with your CV, a brief description of research interest, and why you would like to join our team.