Exercise Reverses Amyloid Beta-Peptide-mediated Cognitive Deficits in Alzheimer's Disease Mice Expressing Mutant Presenilin-2

Med Sci Sports Exerc. 2021 Nov 23. doi: 10.1249/MSS.0000000000002834. Online ahead of print.

Abstract

Purpose: The molecular mechanisms by which physical exercise produces beneficial effects on pathological features and behavioral symptoms of Alzheimer's disease (AD) are not well understood. Herein, we examined whether regular moderate exercise could improve cognitive function and produce transcriptomic responses in the brain.

Methods: Four groups of mice were studied: non-transgenic control (Non-Tg), mice expressing the human presenilin-2 wild type (Tg-PS2w), mice expressing the human presenilin-2 with the N141I mutation (Tg-PS2m), and Tg-PS2m that were subjected to treadmill exercise (TE) at a speed of 10 m/min for 50 min/day, 5 days/week, for 6 weeks (Tg-PS2m/Ex).

Results: Tg-PS2m/Ex mice exhibited increased preference in exploring a novel object than Tg-PS2m in the novel object recognition test (NORT), whereas differences observed in the water maze test and passive avoidance test were not significant. Western blot and histological analyses using amyloid oligomer (A11) and Aβ (6E10) antibody indicated that amyloid oligomer-reactive bands and plaque deposition in the hippocampus were reduced, though not significantly, after TE. Transcriptomic (RNA-sequencing) analysis and subsequent protein analysis revealed that the cell cycle regulatory gene, Cdc28 protein kinase regulatory subunit 2 (Cks2), was decreased, and the cell cycle- and apoptotic cell death-related factors, including cyclin D1, proliferating cell nuclear antigen, and cleaved caspase-3 were increased in the hippocampus of Tg-PS2m, whereas TE reversed their altered expression.

Conclusion: These results support the hypothesis that the pathological features and behavioral symptoms of AD caused by accumulation of amyloid beta-peptide in hippocampus, causing aberrant cell cycle re-entry and apoptosis, can be reversed by regular exercise.