Effects of the Pentapeptide P33 on Memory and Synaptic Plasticity in APP/PS1 Transgenic Mice: A Novel Mechanism Presenting the Protein Fe65 as a Target.

Titanilla Szögi,Miklós Sántha,Ildikó Schuster,Zsolt Bozsó,Lívia Fülöp,Emőke Borbély,Róbert Rajkó,Botond Penke,János Gera,Andrea Gyebrovszki

doi:10.3390/ijms20123050

Abstract

Regulated intramembrane proteolysis (RIP) of the amyloid precursor protein (APP) leads to the formation of fragments, among which the intracellular domain of APP (AICD) was also identified to be a causative of early pathological events. AICD-counteracting proteins, such as Fe65, may serve as alternative therapeutic targets of Alzheimer’s disease (AD). The detection of elevated levels of Fe65 in the brains of both human patients and APP transgenic mice may further strengthen the hypothesis that influencing the interaction between Fe65 and APP may have a beneficial effect on the course of AD. Based on a PXP motif, proven to bind to the WW domain of Fe65, a new pentapeptide was designed and tested. The impedimental effect of P33 on the production of beta amyloid (Aβ) (soluble fraction and aggregated plaques) and on the typical features of the AD pathology (decreased dendritic spine density, synaptic markers, elevated inflammatory reactions) was also demonstrated. Significant enhancements of both learning ability and memory function were observed in a Morris water maze paradigm. The results led us to formulate the theory that P33 acts by altering the conformation of Fe65 via binding to its WW domain, consequently hindering any interactions between Fe65 and key members involved in APP processing.

Highlights

During the last decade, proteolytic products of the amyloid precursor protein (APP) different from beta amyloid (Aβ) became the targets of Alzheimer’s disease (AD) research, as Aβ could not be proven to possess a decisive role in the AD pathomechanism
The so-called regulated intramembrane proteolysis (RIP) [1] of APP requires the concerted action of proteases, as well as many intracellular proteins that bind to the intracellular domain of APP (AICD)
The titration of the Fe65-WW domain with P33 at 310 K resulted in the dissociation constant Kd = 4.68 ± 0.04 μM, calculated from the binding isotherm (Figure 3a)

Summary

Introduction

Proteolytic products of the amyloid precursor protein (APP) different from beta amyloid (Aβ) became the targets of Alzheimer’s disease (AD) research, as Aβ could not be proven to possess a decisive role in the AD pathomechanism. The so-called regulated intramembrane proteolysis (RIP) [1] of APP requires the concerted action of proteases (secretases), as well as many intracellular proteins that bind to the intracellular domain of APP (AICD). AICD is formed both in the amyloidogenic and non-amyloidogenic pathways, and its interactome is wide and complex

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Conclusion