Proteasome Activity Involved in the Modifications of APP Metabolism and the Induction of Alzheimer Pathology

BESSONE IVAN; SAEZ, TRINIDAD M.; ALLOATTI M; OTERO, MARÍA GABRIELA; FALZONE, TOMÁS LUIS; HALLBERG ALAN ; REHEN STEVENS

Londres

Congreso; Alzheimer Association International Conference 2017; 2017

Alzheimer Association

Background: Long lasting cells such as neurons depend on the correct protein homeostasis achieved byprotein synthesis and degradation. Distant local defects in protein accumulation lead to synaptic declineand neurodegeneration. The ubiquitin?proteasome pathway is a master regulator of protein degradationwithin neurons. Interestingly proteasome inhibition has been associated with abnormal protein accumulationand aggregation in Alzheimer Disease. Therefore it is important to understand the role of the proteasome inAPP metabolism and the pathogenic mechanisms induced by its defects. Methods: The effect ofproteasome inhibition on APP were studied in primary mouse cultures related with its axonal transport,processing and local accumulation within neurons. rt-PCR were performed to evaluate the levels of APPmRNA associated with proteasome inhibition. Cerebral organoids generated from human derived neuronswere generated and characterized to be used as a model for understanding disease and pathology. 40 daysoldcerebral organoids were evaluated for APP metabolism and tau behavior in control condition and afterproteasome is inhibited. Results: Proteasome inhibition induces a marked and selective decrease in fulllength APP levels. These changes in APP levels are correlated with significant defects in APP axonaltransport under proteasome inhibition. mRNA analysis do not revealed significant changes in APPexpression under this treatment. Human cerebral organoids can be used as system to test for drugtreatment to understand disease pathology or pathogenic mechanisms associated with changes in APPand tau protein levels or modifications. Conclusions: Our experiments revealed that proteasomeimpairments can induce similar imapirments both at the level of APP metabolism or by tau changes that areassociated with the exacerbation of pathology in many neurodegenerative diseases such as AD.