Objective: To examine the possible neurorestorative effects of chronic rapamycin treatment in AAV-mediated alpha-synuclein (a-syn) overexpression model of Parkinson’s disease (PD), designed to induce hippocampal synucleinopathy to recapitulate cognitive decline of the disease.

Background: Pathological aggregation of a-syn plays a key role in the neurodegenerative process of PD. The spread of a-syn pathology in the hippocampus may lead to cognitive dysfunction which is mostly seen in advanced stages of PD. Rapamycin, the inhibitor of mTOR, is a drug that can activate the autophagic pathway and promote the cleaning of protein aggregates.

Method: Female SD rats were stereotactically injected with AAV-carrying human-a-syn bilaterally into substantia nigra (SN) and dentate gyrus (DG). The alpha-synuclein injected or unlesioned animals were treated with either rapamycin (3mg/kg/day, i.p., n=10, n=6) or vehicle (n=10, n=6), respectively, for 3 days/week from 10^th to 18^th week. Further eight animals were used as naïve controls. Animals were tested for motor and cognitive functions. Brain samples were semi-quantitatively analyzed for a-syn, NeuN, tyrosine hydroxylase (TH), synaptophysin, p62, beclin 1 and caspase 3 expression by immunoblotting (Ethics permission no:2014/51-08).

Results: Rapamycin-treated a-syn group displayed better spatial learning and short-term memory in Morris water maze and novel object recognition tests, respectively, compared to naïve controls (p<0.05). However, rapamycin worsened the motor performance compared to controls in rotarod and locomotor activity test (p<0.05). Rapamycin treatment decreased a-syn overexpression compared to vehicle treatment (p<0.05). Levels of striatal TH and hippocampal NeuN were similar between vehicle and rapamycin groups but synaptophysin levels were lower in the vehicle group compared to controls. Autophagy activation markers p62 and beclin 1 levels were higher in rapamycin-treated a-syn group compared to controls (p<0.05), caspase-3 levels increased in both vehicle and rapamycin groups.

Conclusion: Simultaneous alpha-synuclein overexpression in SN and DG led to cognitive and motor dysfunction and synaptic loss in the hippocampus and striatum; rapamycin treatment helped to reverse these changes by activating the autophagic pathway.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rapamycin-attenuates-nigral-and-hippocampal-alpha-synuclein-accumulation-in-aav-mediated-alpha-synuclein-overexpression-model-of-parkinsons-disease/