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[F3–06–03]: MECHANISMS OF MAM DYSFUNCTION IN ALZHEIMER's DISEASE AND OTHER NEURODEGENERATIVE DISEASES
Author(s) -
AreaGomez Estela
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.284
Subject(s) - senile plaques , endoplasmic reticulum , mitochondrion , biology , amyloid precursor protein , microbiology and biotechnology , alzheimer's disease , lipidomics , lipid metabolism , disease , biochemistry , medicine
mitochondrial matrix) by specific genetically encoded ATP probes. Apoptosis sensitivity and autophagy flux were evaluated in SH-SY5Y cells and human FAD fibroblasts by standard biochemical and immunofluorescence-based techniques. Axonal mitochondrial transport was studied in vivo in zebrafish Rohon-Bear sensory neurons expressing a mitochondrial fluorescent protein. Results: Cell respiration and ATP production are reduced in FAD-PS2 experimental models, especially when cells were forced towards high energy requiring pathways. The FAD-PS2-induced Ca2+ dysregulation contributes to these features. These results suggest an unbalanced cell metabolism, potentially connected to impairments in mitochondrial functionality. Moreover, altered apoptosis sensitivity and blocked autophagy are found in FAD-PS2-T122R expressing SH-SY5Y cells and human FAD fibroblasts. The latter pathway results dysfunctional because of a defective processing in the late autophagy phases. Finally, in vivo mitochondrial axonal transport results also affected by FAD-PS2 expression. Conclusions: Our FAD-PS2 models reveal defects in a variety of cell functionalities. Their relationship with the previously described effects of FAD-PS2 expression on Ca2+ homeostasis and ER-mitochondria coupling is suggested. The possibility that the above alterations, more evident in energy-challenged conditions, could be linked to the pathogenicity of FAD-PS2 mutants is discussed.