AD/PD 2021 – Alzheimer Disease

Virtual Conference

Subcommissural organ-spondin-derived peptide restores memory in a mouse model of Alzheimer’s disease

Juliette Le Douce¹, Nathalie Delétage¹, Sighild Lemarchant¹, Yann Godfrin^1,2

Objectives

SCO-spondin is a brain-specific glycoprotein whose secretion starts during embryogenesis and stops after birth in humans. A small peptide derived from this protein, named NX, displays neuroprotective and neuroregenerative properties. Because drugs reducing cognitive symptoms in Alzheimer’s disease (AD) do not altered its progression, NX effect on cognition was evaluated as a:

• Single treatment,
• Combinatory treatment with donepezil (DPZ),
• Rescue treatment following DPZ resistance.

Methods

Mice were injected with Aβ_25-35 intracerebroventricularly to mimic AD and treated as follows:

• NX alone,
• A combination of subactive doses of NX + DPZ,
• DPZ until resistance and then NX.

Several behavioral tests (Y-maze, passive avoidance, Morris water maze) and biochemical analyses of AD biomarkers were performed.

Results

• NX-treated mice displayed a full restoration of all memory-types evaluated. Cognitive recovery by NX was accompanied by a significant beneficial modulation of cerebral levels of AD pathological biomarkers such as hyperphosphorylated Tau, Aβ_1–42, neuroinflammation, oxidative stress and synaptic markers.
• NX/DPZ-treated mice were protected from Aβ_25-35-induced cognitive deficits for 17 weeks without losing efficacy.
• Four weeks after Aβ_25-35 administration, mice were resistant to DPZ. Interestingly, NX administration completely rescued memory loss in DPZ-resistant mice for up to 17 weeks.

Conclusions

These results support the proof of concept of NX for efficacy either alone, in combination or as a rescue treatment to DPZ. NX represents a promising drug-candidate to adjust therapeutic protocols intended for AD patients depending on the stage, tolerance, and treatment duration.