Effect of cholinesterase inhibitor on APP metabolism in platelets

Abstract

Alzheimer's disease (AD) is characterized by a progressive neurodegeneration of the central nervous system (CNS). It is the most common cause of dementia and can contribute to 60-70% of the cases. It is a condition marked by a pathological triad, characterized by accumulation of extracellular aggregates of amyloid beta protein (Aß), originated from proteolytic processes of amyloid precursor protein (APP) that cause senile plaques, intracellular tangles of hyperphosphorylated tau and neuronal loss. Currently the diagnosis of AD is based on the DSM (Diagnostic and Statistical Manual of Mental Disorders - Diagnostic and Statistical Manual of Disorders), however, the final diagnosis can only be made post mortem by brain biopsy. Under normal physiological conditions, the proteolytic processing of APP occurs via non-amyloidogenic by the action of the enzimes ± (ADAM10) and g secretase. Under pathological conditions, APP is cleaved by the amyloidogenic pathway, producing the toxic fragments of Ab42, by the action of ² secretase (BACE1). The platelets have been used as a model of peripheral diagnosis, allowing its use as a peripheral marker of brain metabolism, by reflecting certain physiological processes in the central nervous system. Most of the circulating APP (95%) is present in platelets. Platelets have all enzymatic machinery to produce the fragments of APP via beta secretase (BACE1), alpha secretase (ADAM10) and gamma-secretase. The objective of this study is to verify the effect of donepezil (cholinesterase inhibitor) under APP metabolism. To do so a longitudinal study of 6 months is planned, in which we will evaluate the ratio of APP and the enzimes BACE1, ADAM10 and gamma-secretase in AD patients before starting the medication, 3 and 6 months later. (AU)