Resistance Exercise as a Potential Neuroprotective Strategy in Alzheimer’s Disease


Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the progressive loss of cognitive functions, memory deficits, and motor and behavioral impairments.

The main neuropathological feature of AD is the accumulation of amyloid-beta (Aβ) protein, which leads to the formation of senile plaques and the impairment of synaptic transmission and neuronal function.

This accumulation of Aβ protein also triggers neuroinflammatory responses and neuronal loss, resulting in cognitive decline and the manifestation of clinical symptoms.

In the early stages of AD, before significant memory loss or cognitive impairment occurs, signs of agitation, restlessness, and increased levels of the stress hormone cortisol can already be observed. High levels of stress and corticosteroids have been linked to an increased risk of developing AD and may accelerate disease progression.

Experimental models using transgenic mice to study AD have shown that these animals exhibit Aβ accumulation, plaque formation, elevated plasma corticosterone levels, and hyperlocomotion. It has been suggested that high levels of corticosteroids in the brain of AD animals increase the activation of enzymes responsible for the production of Aβ, leading to the formation of neurotoxic Aβ peptides.

Physical exercise has been associated with a lower risk of dementia and cognitive impairment in aging. Numerous human studies have shown the positive impact of physical exercise in individuals diagnosed with AD, including improvements in memory, attention, verbal fluency, and cognitive function.

In animal models, physical exercise has been shown to improve spatial memory, increase neurogenesis, decrease Aβ deposition, and reduce plaque formation. Evidence suggests that physical exercise is most effective when initiated before or in the early stages of Aβ deposition, as it may help improve cognitive function and modify or even prevent the development of AD.

While most studies focus on aerobic exercises, few have investigated the effects of other modalities such as resistance exercise (RE). RE, which involves progressive overload and resistance training, has been shown to improve muscle mass, strength, balance, functional capacity, and cognitive function in the elderly.

RE also produces neuroprotective effects, such as increased release of neurotrophic factors, immunomodulatory responses, stimulation of neurogenesis and neuroplasticity, and improved memory. Some studies have shown that RE can improve brain function in the elderly and reduce the risk of developing AD and other dementias.

Based on these findings, the present study aimed to evaluate the effects of RE in an AD mouse model. The researchers used an intermittent protocol of RE, which involved climbing a ladder with progressive overload every other day for four weeks. The results showed that compared to non-mutant littermates, the AD mice exhibited higher levels of hippocampal Aβ plaques, increased plasma corticosterone levels, hyperlocomotion, and decreased central crossings in the open field test.

However, the AD mice did not display any memory impairment in the novel object recognition test. Interestingly, the RE intervention normalized these behavioral and molecular alterations observed in the AD mice, reducing the number of Aβ plaques in the hippocampus and increasing the number of microglial cells around the plaques.

The reduction of Aβ plaques in response to RE is consistent with previous studies showing that exercise can alleviate amyloid pathology.

Exercise may downregulate enzymes responsible for Aβ formation, reduce astrogliosis, enhance the expression of Aβ-degrading enzymes, and modulate microglial activity. RE-induced microglial activation around Aβ plaques may serve a protective role by forming a barrier of processes that condense the plaques. Exercise has been shown to shift microglial activity from a pro-inflammatory to an anti-inflammatory state, which may contribute to the reduction of Aβ load.

Furthermore, RE was effective in reducing hyperlocomotion in the AD mice, suggesting that RE has a calming effect on their behavior. Hyperlocomotion is often observed in AD models and can be indicative of increased neuronal excitability and neuroinflammation. The ability of RE to attenuate hyperlocomotion may be related to its anti-inflammatory effects, as exercise has been shown to reduce neuroinflammatory markers and cytokine production.

Additionally, the normalization of plasma corticosterone levels in the AD mice following RE is noteworthy. Elevated corticosterone levels have been associated with cognitive impairment and neurodegeneration in AD. The reduction in corticosterone levels with exercise suggests that RE may regulate the stress response and mitigate the negative effects of chronic stress on AD pathology.

The absence of memory impairment in the AD mice despite the presence of Aβ plaques is an interesting finding. It suggests that the AD mice in this study were still in the early stages of cognitive decline and that RE intervention could potentially delay or prevent the onset of significant memory deficits. This aligns with previous research indicating that exercise initiated before or during the early stages of AD pathology has the greatest impact on cognitive function.

Overall, the findings of this study provide evidence for the beneficial effects of RE in an AD mouse model. The reduction in Aβ plaques, normalization of corticosterone levels, attenuation of hyperlocomotion, and absence of memory impairment suggest that RE has a neuroprotective and cognitive-preserving effect. However, it’s important to note that this study was conducted in mice, and further research is needed to validate these findings in human populations.

In conclusion, physical exercise, specifically resistance exercise, appears to hold promise as a non-pharmacological intervention for AD. Engaging in regular RE may help reduce Aβ plaque deposition, modulate neuroinflammation, regulate stress hormone levels, and improve behavioral outcomes. Incorporating exercise into lifestyle interventions for individuals at risk of or diagnosed with AD could potentially enhance cognitive function and quality of life.

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