Evaluation of purinergic receptors in the comorbidity of bipolar disorder and Alzheimer's Disease

• Grant number: 20/10725-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2020
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Natalia Turrini
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases, AP.TEM
• Associated scholarship(s): 22/05894-9 - Purinergic interference in astrocyte-interneuron communication in social behavior, BE.EP.DD

Abstract

The Bipolar Disorder (BD) represents an important risk factor for the development of Alzheimer's Disease (AD). Recently, the neurobiological factors involved in this comorbidity were reviewed by our group, and the mechanisms of neuroinflammation, mitocondrial disfunction, excitotoxicity and compromised neurogenesis are some of those factors. Changes in the distribution of neuronal and glial populations were observed. Both diseases present altered microglial morphology and function. As in BD, levels of TNF-± and IL-1² are higher in DA when compared with the control group. Excitotoxicity markers, such as glutamate levels, iNOS and nNOS also demonstrate a positive correlation between BD and AD. However, while in bipolar patients the microglial cells are reduced in size, in AD these cells are larger when compared to control individuals. Both diseases are characterized by the presence of high levels of oxidative stress, which can be observed from elevated levels of ROS and 4-HNE produced, promoting the formation of tau protein filaments. Post-mortem brain samples from AD patients also present changes in the expression of genes related to mitochondrial function, as well as changes in the morphology and distribution of mitochondria. As in BD, the profile of neuroinflammation and oxidative stress leads to neurodegeneration, which is aggravated by neurogenic dysfunction. The presence of immature neurons in the dentate gyrus of AD patients demonstrates a pattern of neurogenic dysfunction similar to that observed in bipolar patients. Although AD patients have low neurogenesis during symptomatic disease progression, some studies have shown that in the early stages of the disease there is an increase in neurogenesis as a repair mechanism due to the presence of a mutation that leads to impaired neuronal maturation; as AD evolves, this mechanism is no longer functional and neurodegeneration intensifies. This characteristic corroborates with that observed in CaMKII-± -/+ mice, in which an increase in neurogenesis was observed during the young stage of development. In both diseases, the enzyme CaMKII- ± is related to neurogenic dysfunction, due to reduced expression or activity. In addition, the cognitive dysfunction observed in bipolar patients can be associated with changes in the expression of the ApoE gene, which plays an essential role in the control of neural progenitor and neuronal precursor cells in the dentate gyrus, and is directly related to the development of sporadic AD. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PILLAT, MICHELI MAINARDI; OLIVEIRA-GIACOMELLI, AGATHA; DAS NEVES OLIVEIRA, MONA; ANDREJEW, ROBERTA; TURRINI, NATALIA; BARANOVA, JULIANA; LAH TURNSEK, TAMARA; ULRICH, HENNING. Mesenchymal stem cell-glioblastoma interactions mediated via kinin receptors unveiled by cytometry. Cytometry Part A, v. 99, n. 2, SI, JAN 2021. (18/07366-4, 20/10725-6, 12/50880-4, 19/24553-5, 19/26852-0)

PILLAT, MICHELI MAINARDI; OLIVEIRA-GIACOMELLI, AGATHA; DAS NEVES OLIVEIRA, MONA; ANDREJEW, ROBERTA; TURRINI, NATALIA; BARANOVA, JULIANA; LAH TURNSEK, TAMARA; ULRICH, HENNING. Mesenchymal stem cell-glioblastoma interactions mediated via kinin receptors unveiled by cytometry. Cytometry Part A, v. 99, n. 2, p. 12-pg., 2021-01-13. (12/50880-4, 20/10725-6, 19/24553-5, 19/26852-0, 18/07366-4)

NAALDIJK, YAHAIRA; SHERMAN, LAUREN S.; TURRINI, NATALIA; KENFACK, YANNICK; RATAJCZAK, MARIUSZ Z.; SOUAYAH, NIZAR; RAMESHWAR, PRANELA; ULRICH, HENNING. Mesenchymal Stem Cell-Macrophage Crosstalk Provides Specific Exosomal Cargo to Direct Immune Response Licensing of Macrophages during Inflammatory Responses. STEM CELL REVIEWS AND REPORTS, v. 20, n. 1, p. 19-pg., 2023-10-18. (17/23604-0, 20/10725-6, 12/50880-4, 18/07366-4, 15/14343-2)

OLIVEIRA-GIACOMELLI, AGATHA; PETIZ, LYVIA LINTZMAIER; ANDREJEW, ROBERTA; TURRINI, NATALIA; SILVA, JEAN BEZERRA; SACK, ULRICH; ULRICH, HENNING. Role of P2X7 Receptors in Immune Responses During Neurodegeneration. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 15, MAY 26 2021. (18/08426-0, 19/24553-5, 18/07366-4, 19/26852-0, 20/10725-6)