Premium
P1‐187: AGED CATTLE BRAIN DISPLAYS ALZHEIMER'S‐LIKE PATHOLOGY THAT CAN BE PROPAGATED IN A PRION‐LIKE MANNER
Author(s) -
Moreno-Gonzalez Ines,
Edwards George A.,
Ruiz Nazaret Gamez,
Peter Priyadarshini,
Morales Rodrigo,
Marquez Mercedes,
Pumarola Marti,
Soto Claudio
Publication year - 2018
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.2018.06.191
Subject(s) - prion protein , bovine spongiform encephalopathy , disease , fibril , amyloid (mycology) , protein aggregation , transmissible spongiform encephalopathy , biology , neuroscience , animal model , pathology , chemistry , virology , microbiology and biotechnology , medicine , scrapie , biophysics , endocrinology
Background:Alzheimer’s disease (AD) is the most common form of dementia worldwide. Factors associated with aging contribute majorly to the progression of this disease. Not only extracellular amyloid plaque but intracellular amyloid-b (Ab) also has vital roles behind shaping the disease before the clinical symptoms appear. In this study the major objective was to correlate the chemistry of an aging cell in vitro and in vivo by introducing a very subtle, tolerable amount of DNA damage in cultured neuron or in animal and to find whether this could in turn increase intracellular and extracellular Ab level or not. Methods: PC12 and SHSY5Y cells were differentiated in presence of NGF (50ng/ml) and Retinoic acid (10mM) for five and seven days respectively. Primary cortical neuron culture from 16-18 days old embryo was also done. Camptothecin (CPT) was streotaxically infused in the cortex of a healthy young rat for in vivo studies. Results: Doses of Camptothecin (CPT) starting from 5nM to 10mM was treated in differentiated SH-SY5Y cells for 24h to identify a window of dose which will not be lethal. It was found that upto 100nMCPT for 24h was not causing significant cell death. A sign of very subtle genomic DNA damage, hyperfused mitochondria and interestingly hyperpolarization of mitochondrial membrane was observed from 5nM dose itself. There was also an increased expression of complex-V of electron transport chain. Increased Ab(1-42) level and amyloid precursor protein from 5nM dose of CPT in cultured primary cortical neurons and differentiated SH-SY5Y cells after treatment for 24h was observed.When a very sub-lethal dose of CPTwas introduced in vivo inside the cortex of a healthy young rat for 48h it was found that Ab(1-42) levels were increased in the cortex. Surprisingly there was no increased ROS production under similar condition. Conclusions: Taken together this data suggest that increase of intracellular Ab(1-42) is a very early stress response of a neuron under very subtle genomic DNA damage. Thus we propose that age related subtle genomic DNA damage may lead to increased Ab(1-42) production in an apparently healthy looking neuron way before the clinical symptoms appear.