Subcommissural Organ-Spondin-Derived Peptide Restores Memory in a Mouse Model of Alzheimer's Disease.

Juliette Le Douce,Sighild Lemarchant,Valérie Bourdès,Yann Godfrin,Nathalie Delétage

doi:10.3389/fnins.2021.651094

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of older people worldwide and is characterized by a progressive deterioration of cognitive functions, including learning and memory. There are currently very few approved treatments (i.e., acetylcholinesterase inhibitors such as donepezil), all of which are limited to the symptomatic control of AD and are associated with side effects that may result in discontinuation of treatment. Therefore, there is an urgent need to develop disease-modifying treatments to prevent AD-induced cognitive deficits. Subcommissural organ (SCO)-spondin is a brain-specific glycoprotein produced during embryogenesis and has a substantial impact on neuronal development. In the current study, we sought to evaluate the protective effects of the linear (NX210) and cyclized (NX210c) forms of a SCO-spondin-derived peptide on learning and memory in a mouse model of AD. Mice received an intracerebroventricular injection of Aβ25–35 oligomers and were subsequently treated with intraperitoneal injections of vehicle, NX210 or NX210c of different doses (ranging from 0.1 to 30 mg/kg) and therapy paradigms (early or late stand-alone treatments, combination with donepezil or second-line treatment). Cognitive function was evaluated using Y-Maze, step-through latency passive avoidance (STPA) and Morris water maze (MWM) tests for up to 4 months. Early stage daily treatment with NX210 and NX210c decreased the levels of common pathological markers and features of AD, including Aβ1–42, phosphorylated-tau, inflammation, astrogliosis and lipid peroxidation. Meanwhile, use of these drugs increased the levels of synaptophysin and postsynaptic density protein 95. Regardless of the experimental paradigm used, NX210 and NX210c prevented Aβ25–35-induced decrease in spontaneous alternations (Y-Maze) and step-through latency into the dark compartment (STPA), and Aβ25–35-induced increase in time needed to locate the immersed platform during the learning phase and decrease in time spent in the target quadrant during the retention phase (MWM). Interestingly, this study provides the novel evidence that the native and oxidized cyclic forms of the SCO-spondin-derived peptide reduce pathological factors associated with AD and restore learning and memory at both early and late disease stages. Overall, this study sheds light on the therapeutic potential of this innovative disease-modifying peptide to restore memory function in patients with AD.

Highlights

An increase in the prevalence of chronic diseases, including Alzheimer’s disease (AD), has accompanied the increase in aging population worldwide
By using several biochemical analyses and behavioral tests in different therapy paradigms relevant to clinical conditions, we provide the first evidence of the fact that systemic administration of NX210 or NX210c halts the progression of AD and restores memory function, which is maintained for up to 4 months, in a mouse model
Stage daily treatment with NX210 and NX210c restored Aβ25-35-induced spatial learning and memory deficits, as shown by the decreased time to find the platform during the learning phase and the increased time spent in the target quadrant (T) versus other quadrants (O) during the retention phase in the Morris water maze compared with Aβ25-35-injected mice treated with vehicle

Summary

Introduction

An increase in the prevalence of chronic diseases, including Alzheimer’s disease (AD), has accompanied the increase in aging population worldwide. Available pharmacological treatments are effective in reducing symptoms but not curing them Among these treatments, studies have supported the efficacy of donepezil in symptom reduction, which is considered the mainstay treatment for patients with mild to severe AD despite dose-dependent adverse effects and modest clinical efficacy in treating cognitive decline (Tsoi et al, 2016; Arvanitakis et al, 2019; Haake et al, 2020). Numerous antiAD agents (>100) are being developed, there are currently no approved disease-modifying treatments (Cummings et al, 2019). This represents a major limitation in the attempt to reduce the rate of progression of AD pathology, which is necessary to reduce functional and cognitive deficits that result from AD. Efforts have been made to develop effective therapeutics at preclinical and clinical stages; among these, almost 30 anti-amyloid and anti-tau agents are in phase 3 (Breijyeh and Karaman, 2020; Haake et al, 2020; Zhang et al, 2020)

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