Analysis of the interaction between endoplasmic reticulum and mitochondria in a cell model of Alzheimer's disease

• Grant number: 20/03665-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2020
• End date: May 31, 2022
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Merari de Fátima Ramires Ferrari
• Grantee: Caio José Machado da Veiga
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Alzheimer's disease (AD) is a neuropathology caused by neuron death and loss of synapses, and is recognizable as dementia or cognitive dysfunction. The main alterations that occur in neurons and lead to the neuropathological injuries are the cumulation of extracellular plaques mainly made out of amyloid-beta peptide and the formation of neurofibrillary tangles caused by tau protein hyperfosforilation. The homeostasis of intracellular organelles such as the endoplasmic reticulum (ER) and mitochondria is impaired during development of AD. ER fragmentation can be identified before neuron dysfunction and leads to significant loss of protein synthesis and calcium homeostasis. Mitochondria interact with the ER during its biogenesis and these organelles exchange calcium ions continuously, both contributing to calcium homeostasis. In the initial stages of AD there are changes in the membrane contact sites between ER and mitochondria, which induces metabolic dysfunction and the formation of toxic proteins in higher amounts. With these evidences, the hypotheses of this project is that during development of the neuropathology there are early changes in mitochondria and ER morphology in neurons, and also alterations in the contact sites between the two organelles. The study is going to be done in neuronal cells differentiated from N2a cells expressing mutant Tau P301L as a cellular model of protein aggregation related to Alzheimer Disease. Endoplasmic reticulum and mitochondria will be evaluated through the use of specific fluorescent probes for the organelles. We wish to contribute to the current explanation of the initial processes which lead to the neuropathological injuries usually seen in AD. (AU)