Evaluation of the biological function of SPTLC3 and ceramid metabolism in the progression of Alzheimer's disease in neural cell culture and APP/PS1 mice.

• Grant number: 23/02751-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2024
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Eduardo Rochete Ropelle
• Grantee: Ana Paula Morelli
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil

Abstract

Alzheimer's disease is a progressive and fatal neurodegenerative disorder which manifests especially by cognitive, behavioral and motor deterioration. The disease is considered a global priority of public health, both by the poor prognosis associated with the significant health commitment and the lack of effective treatments in disease management. The disease is especially characterized by the formation of amyloid plaques, and by the neurofibrillary tangles formation, generated especially by hyperphosphorylation of Tau protein. It is known that different molecular pathways are associated with the Alzheimer's disease etiology, such as protein synthesis and degradation shortcoming, altered glucose metabolism, mitochondrial dysfunction and inflammation, but failures in lipid metabolism have been currently reported as crucial in Alzheimer's disease neurodegeneration . Among lipids, ceramids play important roles in multiple biological processes involved in Alzheimer's disease, such as cell proliferation and differentiation, apoptosis, insulin resistance, oxidative stress, senescence and inflammation and the SPT family is the responsible for the primary synthesis of ceramides. Studies report that inhibition of SPT proteins using myriocin reduced insulin resistance in murine myoblast cell culture and reduced the formation of atherosclerotic plates in APOE-/- mice. Accordingly, a previous bioinformatics analysis performed by our group showed that the isoform 3 of SPT is the most increased in patients with the Alzheimer's disease. In addition, SPTLC3 correlated positively with genes related to cell death and inflammation and negatively to genes related to mitochondria and synaptic transmission. Thus, the present study aims to characterize the biological role of SPTLC3 and ceramid metabolism in the progression of Alzheimer's disease. Hypothalamus and hippocampal cell cultures and APP/PS1 mice will be used to validate the hypothesis. The present project aims to develop SPTLC3KO (Knockout) strains and overexpress the gene to determine its function in the synthesis and ceramids metabolism, as well as the association with Alzheimer's disease markers such as APP, Tau, and ²-amyloid. The study aims to evaluate the effect of myriocin treatment, a ceramid synthesis inhibitor, on Tau phosphorylation and ²-amyloid accumulation in the hipocampus of APP/PS1 mice. Analyzing the biological role of SPTLC3 and its relationship with associated metabolic pathways can be critical to evaluate the genesis and progression of Alzheimer's disease, as well as unveal new treatment perspectives for this disease.