Effects Of Alzheimer’s Disease Associated Protein Presenilin 1 On Mitochondrial Dynamics And Function

Alzheimer’s disease(AD),a progressive neurodegenerative disease,is the most common form of dementia.Patients with Alzheimer’s disease begin with memory and cognitive decline,which gradually progresses to loss of verbal and spatial cognition.There are two major pathological markers of Alzheimer’s disease:Amyloid β plaques and Neurofibrillary tangles(NTFs).Recent studies have shown that impaired mitochondrial function and dynamics play a crucial role in the pathogenesis of neurodegenerative diseases.In patients with AD,mitochondrial damage in neurons is earlier than the formation of amyloid plaques,which indicates that mitochondrial dysfunction play a key role in the pathological process of AD.The vast majority of AD is sporadic,and only a very small number of patients have familial AD involving inherited mutations.Among patients with familial AD,the most common gene mutations are those involving APP,PSEN1,and PSEN2.The psenl gene encoding Presenilinl(PS1)protein is a subunit of gamma secretase,its main function is as a catalytic subunit gamma secretase.In recent years,many studies have shown that the PS1 protein and mitochondria are very closely linked,in view of the PS1 protein and mitochondria play a key role in ad pathology,PS1 and very worthy of our in-depth research on the relationship between mitochondria.First of all,we found through the immunofluorescence PS1 co-localized with mitochondrial.At the same time we determined the PS1 N-terminal fragment located in the mitochondria via direct isolation of mitochondria.Furthermore we re-expression N terminal flag labeled PS1 in PS1KO HEK293 cells,and detected the N terminal fragment of PS1 in the purified mitochondria component.In order to understand the effect of PS1 on mitochondria,we first analyzed the effect of PS1 on mitochondrial dynamics in HEK293 cells.We found that PS1 knockout did not impact the mitochondrial morphology of HEK293 cells,while overexpression of PS1 or its wild-type mutation would result in reduced mitochondrial number and over-fusion.Meanwhile,we found that knockout of PS 1 would affect the mitochondrial function of HEK293 cells:knockout of PS1 would result in reduced mitochondrial membrane potential of the cell and reduced ATP synthesis also results in down-regulation of respiratory chain complex Ⅳ and complex Ⅱ protein levels.In order to further proven PS1 affect mitochondrial dynamics and function mechanism,we tested the PS1 is associated with mitochondrial protein interaction By Co-IP experiments.Then we found that PS1 interaction with DRP1 which is a mitochondrial fission protein,further experiments to determine the PS1 N-terminal first 80 amino acids is the key domain to the interaction between the PS1 and DRP1.PS1 is a key protein in familial AD.It participates in multiple metabolic processes in cells,and participates in multiple signaling pathways that regulate growth and development.Our experimental results show that PS1 is closely related to the dynamics and functions of mitochondria.Recent studies have also shown that mitochondrial damage is in the pathological mechanism of AD.Therefore,probing the influence of PS1 on mitochondrial function may provide a new idea for clarifying the pathological mechanism of AD.