Differential effects and underlying mechanisms of voluntary, forced, and combined exercise on ameliorating...

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effective therapeutic drugs available for AD. Regular exercise training has emerged as a promising physical intervention strategy for mitigating both the risk and progression of AD, but different types of exercise interventions show varied and conflicting results in AD treatment, with their differential effects and mechanisms still unelucidated.

Using an Aβ oligomer-induced AD mouse model, we investigated therapeutic effects of voluntary wheel running, forced treadmill running, and combined exercise (voluntary combined with forced running) on AD pathologies. For depressive-like behavior, we conducted forced swimming test and tail suspension test; for cognition, Novel object recognition test (object recognition ability) and Morris water maze test (spatial learning and memory) was used respectively. We applied BrdU-DCX/NeuN/GFAP immunofluorescence co-staining to measure neurogenesis, Western blot to examine proteins associated with synapses, neurons, astrocytes, apoptosis, and BDNF signaling key components, serum metabolomics to identify exercise-induced metabolites. Furthermore, a clinical trial involving healthy subjects and patients with AD implemented an acute exercise intervention and utilized portable functional near-infrared spectroscopy to assess cortical activation and functional connectivity under conditions of both voluntary and forced exercise.

Voluntary, forced, and combined exercise alleviated depressive-like phenotypes and short-term cognitive deficits in AD mice, while only forced exercise conferred sustained long-term memory benefit. All exercises boosted hippocampal neurogenesis by enhancing newborn cell (BrdU⁺ cells) proliferation, promoting differentiation into immature neurons (BrdU⁺DCX⁺ cells), and maintaining newborn astrocytes (BrdU⁺GFAP⁺ cells). Forced/combined exercise sustained immature neurons (DCX⁺ cells), and forced exercise alone significantly elevated mature newborn neurons (BrdU⁺NeuN⁺ cells). Neuroprotective mechanisms may involve the modality-specific BDNF-TrkB signaling and BAX-dependent apoptosis regulation. Exercise-induced metabolites (amino acid homeostasis, energy provision, oxidative defense) strongly correlated with neurogenesis and neural function. In AD patients, acute voluntary exercise was associated with enhanced left prefrontal cortex activity, whereas acute forced exercise increased bilateral motor cortex activation.

Our findings reveal distinct neuroprotective profiles of long-term voluntary, forced, and combined exercise interventions against Aβ oligomer neurotoxicity in an AD mouse model, and different acute exercise modalities also demonstrate distinct effects on cortical activation and functional connectivity in patients with AD. Our study provides novel insights into exercise modalities' therapeutic effects in ameliorating AD neuropathology.