Mechanistic and Causative Role of p17 in Mediating Endogenous Neuroprotective Mitochondrial Stress Response in Neurodegeneration and Brain Injury. Mitochondria are major subcellular components essential for proper cellular functioning and survival, and recent studies have strongly implicated mitochondrial dysregulation as a significant driver of the secondary deleterious cascades following TBI and related disorders, including chronic traumatic encephalopathy (CTE). Our recent studies revealed that a newly discovered transporter called p17 mediates the trafficking of ceramide synthesis-1 (CerS1) and induces C18-ceramide synthesis and mitophagy in the mitochondrial membrane, which acts as an elimination signal for damaged mitochondria and thereby promotes both in vitro and in vivo neuronal survival, which could help prevent neurodegeneration after brain injury and beyond.
Karakaya, E.*, Oleinik, N.*, Edwards, J., Tomberlin, J., Barker, R.B., Berber, B., Ericsson, M., Alsudani, H., Ergul, A., Beyaz, S., Lemasters, J.J., Ogretmen, B., and Albayram, O. (2024) p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury. PNAS Nexus 3(2):pgae018. (* Equal contribution)
Oleinik, N., * Albayram O., * Kassir, M.F., Atilgan, F.C., Walton, C., Karakaya, E., Kurtz, J., Alekseyenko, A., Alsudani, H., Sheridan, M., Szulc, Z.M., Ogretmen, B. (2023) Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects. Aging Cell. e13954. (*Equal contribution)
Albayram O#, Albayram S, Mannix R. (2020) Chronic traumatic encephalopathy-a blueprint for the bridge between neurological and psychiatric disorders. Transl Psychiatry. 10(1):424. (#Corresponding author)
Albayram, O., MacIver, B., Mathai, J., Verstegen, A., Baxley, S., Qiu, C., Bell, C., Caldarone, B.J., Zhou, X.Z., Lu, K.P., Zeidel, M. (2019) Traumatic Brain Injury-related voiding dysfunction in mice is caused by damage to rostral pathways, altering inputs to the reflex pathways. Scientific Reports 9(1):8646.
Albayram, O., Kondo, A., Mannix. R., Smith, C., Li, C., Tsai, C.Y., Herbert, M.K., Qiu, J., Monuteaux, M., Driver, J.A., Yan, S., Gormley, W., Puccio, A.M., Okonkwo, D.O., Lucke-Wold, B., Bailes, J., Meehan, W., Zeidel, M., Lu, K.P. and Zhou, X.Z. (2017) Cis P-tau, induced after clinical neurotrauma, is a druggable target in preclinical neurotrauma models. Nature Communication 8(1):1000.
Kondo, A., Shahpasand, K., Mannix, R., Qiu, J., Moncaster, J., Chen, C. H., Yao, Y., Lin, Y. M., Driver, J. A., Wei, S., Man-Li, M., Albayram, O., Huang, P., Rotenberg, A., Ryo, A., Goldstein, L. E., Pascual-Leone, A., Mckee, A., Meehan, M., Zhou, X. Z., and Lu, K. P. (2015) An early driver of traumatic brain injury and neurodegeneration that can be effectively blocked by antibody. Nature 523(7561), 431-6.
Mechanisms Underlying the Distinct Age-Dependent Effects of the Endocannabinoid Systems Activity in the Brain. During brain aging, the expression levels and the distribution of cannabinoid components are altered, indicating that the endocannabinoid system may contribute to the physiological and behavioral changes associated with aging. Our studies demonstrated that a chronic low dose of THC restored the normal age-related decline of cognitive performance in old animals to the level of young mice associated with increased synapse densities, upregulation of anti-aging genes, and long-lasting induction of intracellular cascades due to epigenetic changes. We are now focused on studying cellular and molecular mechanisms underlying age-dependent changes of endogenous brain cannabinoid system activities in normal and pathological brains. Knowledge gained from these studies will be instrumental in exploring the significance of age-mediated substance exposure on psychiatric and neurodegenerative disorders, which will help to identify the controversy and translational failures in studies primarily using young-adult subjects.
Endocannabinoid Signaling for GABAergic-Microglia (Mis)Communication in the Brain Aging. (2021) Carrera J, Tomberlin J, Kurtz J, Karakaya E, Bostanciklioglu M, Albayram O. Frontiers Neuroscience 14:606808.
Ativie F, Komorowska JA, Beins E, Albayram Ö, Zimmer T, Zimmer A, Tejera D, Heneka M, Bilkei-Gorzo A. (2018) Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity. Frontiers Molecular Neuroscience. 11:295.
Bilkei-Gorzo, A., * Albayram, O.,* Draffehn, A., Michel, K., Piyanova, A., Oppenheimer, H., Dvir-Ginzberg, M., Rácz, I., Ulas, T., Imbeault, S., Bab, I., Schultze, J.L., Zimmer, A. (2017) A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nature Medicine 23(6), 782-787. (* Equal contribution) (Cover story; and News and Views Comments in Nature Med. 12: 392-393. PMCID: NA.
Albayram, O., Passlick, S., Bilkei-Gorzo, A., Zimmer, A., Steinhauser, C. (2016) Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons. European Journal of Physiology (Pflugers Arch.) 468(4), 727-37.
Albayram, O., Bilkei-Gorzo, A., Zimmer, A. (2012) Loss of CB1 receptors leads to differential age- related changes in reward driven learning and memory. Frontiers in Aging Neuroscience 4(34), 1-8.
Albayram, O., Alferink, J., Pitsch, J., Piyanova, A., Neitzert, K., Poppensieker, K., Mauer, D., Michel, K., Legler, A., Becker, A., Monory, K., Lutz, B., Zimmer, A., Bilkei-Gorzo, A. (2011) Role of CB1 receptors on GABAergic neurons in brain aging. PNAS. 108(27), 11256-61.
Mechanistic Role of Meningeal Lymphatic Vasculature and Immunity in the Brain, Aging and Neurodegenerative Diseases. Historically, the brain was considered an immune-privileged organ separated from the peripheral lymphatic system by the blood-brain barrier. Currently, meningeal lymphatics in the brain have garnered increasing attention in the scientific literature, which has left us to investigate how the lymphatic vasculature network may be positioned within the dural matters in the brain and the novel potential role of the meningeal lymphatic system in brain aging and age-related neurodegenerative disorders. Recently, we have demonstrated progressive age-related cervical lymph node atrophy and thickening of lymphatics channels in the human brain's dorsal and ventral regions. These findings reflect the reduced lymphatic output of the aged brain, which results in deleterious immune and cerebrovascular responses that contribute to the development and progression of age-dependent neurological disorders such as Alzheimer's disease and related dementias. We are now investigating to develop novel strategies to detect meningeal lymphatic vasculature in humans and translational therapeutic interventions to prevent age-associated neurodegeneration by improving brain lymphatic drainage.
Albayram S, Smith G, Tufan F, Tuna IS, Bostanciklioglu M, Zile M & Albayram O. (2022). Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes. Nature Communication, 13(1), 203.
Keser Z, Smith G, Cagil E, Tufan F, Albayram O, Albayram MS (2023) High-resolution MRI to noninvasively characterize drainage around the carotid artery into the cervical lymph nodes. J Neuroimaging. 33(1):102-108.
Albayram MS, Smith G, Albayram O. (2023) Reply to: Fluid signal suppression characteristics of 3D-FLAIR with a T2 selective inversion pulse in the skull base. Nature Communication. 14(1):4914.
Albayram MS, Smith G, Albayram O. (2023) Reply to: The pitfalls of interpreting hyperintense FLAIR signal as lymph outside the human brain. Nature Communication. 14(1):4912.
Qiu, C.,*, Albayram O.,* Kondo, A., Wang, B., Kim, N., Arai, K., Tsai, C.Y., Bassal, M.A., Herbert, M.K., Washida, K., Angeli, P., Kozono, S., Stucky, J.E., Baxley, S., Lin, Y.M., Sun, Y., Rotenberg, A., Caldarone, B.J., Bigio, E.H., Chen, X., Tenen, D.G., Zeidel, M., Lo, E.H., Zhou, X.Z., Lu, K.P. (2021) Cis P-tau underlies vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice. Science Translational Medicine. 13(596): eaaz7615. (* Equal contribution).