Title

 

Authors

E. Marcello
 
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.

 

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia and no cure is availableat the moment. AD-underlying neuropathology includes extracellular deposition of beta-amyloid  peptide (Aβ), intraneuronal accumulation of aberrant forms of hyperphosphorylated Tauaswellassynapse and neuronalloss. Synapselossis an early and invariantfeature of the disease and underlies the memoryimpairmentevident in AD patients. Molecularpathwayleading to synapseloss and dysfunction are notwellunderstood and are difficult to monitor in AD models. A cell-permeable peptide strategy, designed to interfere with the complexbetween ADAM10, the main α-secretase candidate, and its partner, SAP97, a protein of the MAGUK family, wasused to generate a non-transgenicanimal model of Alzheimer'sdisease. Association of ADAM10 to SAP97 governsenzymetrafficking and activityatsynapticsites.Interfering with ADAM10/SAP97 complex for two weeks by means of cell-permeablepeptidesissufficient to shift APP metabolismtowardsamyloidogenesis and allows the reproduction of initialphases of sporadicAlzheimer’sdisease. Aftertwo weeks of treatment, wedetected progressive Alzheimer’s-likeneuropathology, with an increase of Amyloid-βaggregates production and of Tau hyperphosphorylation and a selectivealteration of NMDA receptorsubunitcomposition in the post synapticcompartment of mouse brain. Behavioral and electrophysiologicaldeficitswerealsoinduced by peptide treatment, thusprovingthisstrategyuseful to model earlystages of the disease in mice. In conclusion, our model can be used to study pathogenic consequences of a specific pathway of AD pathogenesis (ADAM10/SAP97 disruption), characteristic of the early stages of sporadic disease. This approach offers the unprecedented possibility to interfere with endogenous APP processing in adult mice neither overexpressing proteins derived from inherited forms of the disease nor altering developmental processes. Moreover, it can be useful to study the convergence as well as the temporal correlation of multiple neuropathological pathways, such as Aβ production and synaptic dysfunction, and, eventually, to investigate new therapeutic strategies.