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

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.

Safety, Tolerability, Pharmacokinetics and Initial Pharmacodynamics of a Subcommissural Organ-Spondin-Derived Peptide: A Randomized, Placebo-Controlled, Double-Blind, Single Ascending Dose First-in-Human Study

“…Besides tryptophan and homocysteine, the PD analysis showed increasing and decreasing variations for the plasma levels of glutamine and glutamate, respectively, at 10 h in participants treated with NX210/NX210c (data not shown). Recently, studies demonstrated the neuroprotective action of NX210c against glutamate-induced excitotoxicity in primary rat cortical and hippocampal neurons, as well as human cortical neurons [ 9 , 10 ]. Interestingly, glutamate (a major excitatory neurotransmitter) is highly abundant throughout the brain; it plays a crucial role in neuronal plasticity and the maintenance of cognitive processing.…”

“…Owing to oxidation and the consequent formation of an intrachain disulfide bridge between the two cysteines, the peptide can take a cyclic conformation and is termed cyclic NX210 (NX210c). Preclinical in vitro and in vivo data have shown that NX210 exhibits important properties, which may be suitable for the treatment of neurological disorders in humans (i.e., neuroprotection, neuroregeneration, induction of remodeling and cellular plasticity mechanisms, and anti-neuroinflammatory action) [ 8 , 9 ]. This includes data showing that NX210/NX210c prevents glutamate-related cell death (excitotoxicity) in various primary neuronal cell types of human or rodent origin [ 10 ].…”

“…As recently reported, in a mouse model of AD induced by the intracerebroventricular injection of Aβ 25–35 oligomers, NX210/NX210c fully restored spatial working and contextual long-term memories. This therapeutic effect was sustained for up to 4 months [ 9 ]. Owing to its pleiotropic properties, NX210 targets cognitive disorders (e.g., neurodegenerative diseases) [ 9 ] as well as CNS injuries (e.g., traumatic brain or spinal cord injuries) [ 8 ].…”

“…This therapeutic effect was sustained for up to 4 months [ 9 ]. Owing to its pleiotropic properties, NX210 targets cognitive disorders (e.g., neurodegenerative diseases) [ 9 ] as well as CNS injuries (e.g., traumatic brain or spinal cord injuries) [ 8 ]. In addition, a CNS biodistribution study following a single intravenous administration of [ 3 H]NX210c to male non-pigmented rats suggested that NX210c passes through the blood–cerebrospinal fluid (CSF) barrier.…”

SCO-spondin, a giant matricellular protein that regulates cerebrospinal fluid activity

“…It has also been proposed that the progressive atrophy of human SCO with the subsequent lack of SCO-spondin may be contributing to the failure of human adult neurons to repair in CNS injuries or diseases [ 76 ]. In this way, a peptide derived from the first TSR domain of SCO-spondin protects neurons from glutamate-induced excitotoxicity [ 76 ] and restore learning and memory in a mouse model of Alzheimer’s disease [ 188 ].…”