Se-Methylseleno-L-Cysteine Interferes With Alzheimer's Disease Pathogenesis By The Regulation Of Authophagy And Mitochondria

Alzheimer's disease(AD)is an age-related neurodegenerative disease,which is characterized by memory loss and cognitive impairment.The primary pathological features of AD are A? deposition to form senile plaques and excessive tau protein phosphorylation to generate neurofibrillary tangles(NFT).Moreover,dyshomeostasis of metal ions and dysfunction of mitochondria and autophagy accelerated the development of AD pathology,which promoted A?aggregation,tau phosphoylation,and finally resulted in the irreversible synaptic loss and neuronal damage.As a vital trace element,selenium(Se)is essential for proper brain function and may be beneficial in reducing Alzheimer's pathology.Se-methylselenocysteine(SMC),a naturally occruing organoselenium compound found in many kinds of plants,has lower toxicity but better bioavailability than inorganic selenocompound.Studies on SMC are mainly focused on its anti-cancer or anti-oxidant activity,its potential in neurodegenerative disorders including AD has remained elusive.In this study,we examined the potential effects of SMC on triple transgenic AD(3×Tg AD)mice using the methods of Morris water maze,open field test,western blot analysis,ICP-MS,SR-XRF,Gallys staining,Nissl's staining and mitochondria time-lapse imaging,etc.AD model mice were treated with 3 ?g/ml SMC in drinking water for 12 months starting from 2-month age.We found: 1)SMC improved spatial learning and memory deficits of 3×Tg AD mice;2)SMC treatment significantly reduced A? and tau pathology,and subsequently preserved neuronal activity and synaptic proteins in the brains of 3×Tg AD mice;3)SMC modulated the levels and distribution of several metal ions in AD mouse brains;4)SMC promoted autophagy and the generation of autophagolysosome by regulation the activity of m TOR;5)SMC stimulated Mito biogenesis and inhibited Mito apoptosis by activation of AKT,promoted ATP generation by increasing the expression of energy metabolism related proteins,maintained balance between Mito fission and fusion,improved the Mito mobility in the neuronal axons,and protected Mito membrane potential and m PTP.In sum,our study suggested SMC as a promising compound for the prevention or intervention of AD.