Exercise mimetics: a novel strategy to combat neuroinflammation and Alzheimer's disease

Abstract

Neuroinflammation is a pathological hallmark of Alzheimer's disease (AD), characterized by the stimulation of resident immune cells of the brain and the penetration of peripheral immune cells. These inflammatory processes facilitate the deposition of amyloid-beta (Aβ) plaques and the abnormal hyperphosphorylation of tau protein. Managing neuroinflammation to restore immune homeostasis and decrease neuronal damage is a therapeutic approach for AD. One way to achieve this is through exercise, which can improve brain function and protect against neuroinflammation, oxidative stress, and synaptic dysfunction in AD models. The neuroprotective impact of exercise is regulated by various molecular factors that can be activated in the same way as exercise by the administration of their mimetics. Recent evidence has proven some exercise mimetics effective in alleviating neuroinflammation and AD, and, additionally, they are a helpful alternative option for patients who are unable to perform regular physical exercise to manage neurodegenerative disorders. This review focuses on the current state of knowledge on exercise mimetics, including their efficacy, regulatory mechanisms, progress, challenges, limitations, and future guidance for their application in AD therapy.

Fig.1

Neuroinflammation activation. TLRs are a family of membrane-bound receptors that recognize and bind to PAMPs. Upon binding to PAMPs, TLRs recruit adaptor molecules such as MyD88, that form a molecular complex called Myddosome. The complex activates a subsequent kinase cascade, which leads to the release of NF-κB from the cytoplasm and translocation to the nucleus, where it regulates the expression of genes involved in inflammation, such as IL-1β and TNF-α. NLRs are a group of cytosolic receptors and sense DAMPs and PAMPs that enter the cell. When they detect pathogens, NLRs undergo oligomerization and recruit ASC to assemble the NLRP3 or NLRC4 inflammasome. The filamentous ASC then attracts pro-caspase 1, which becomes activated and cleaves pro-IL-1β into mature cytokines. Additionally, in the context of AD, Amyloid aggregation and Tau hyperphosphorylation can facilitate the formation of NLRP3 inflammasome leading to microglial activation. The interaction between Aβ and microglia activation is involved in diverse molecular signaling such as the TREM2–TYROBP axis. AP, adaptor proteins; DAMPs, danger-associated molecular patterns; PAMPs, Pathogen-associated molecular patterns; TLRs, Toll-like receptors; TNF-α, Tumor necrosis factor-alpha; ASC, Apoptosis-associated speck-like protein containing a CARD; NLRP3, NOD-like receptor family pyrin domain containing 3; NLRPC4, NOD-like receptor family CARD domain-containing protein 4; AD, Alzheimer's disease; Aβ, amyloid beta; TREM2, triggering receptor expressed on myeloid cells 2; TYROBP, tyrosine kinase binding protein; GDMD: gasdermin D

Fig. 2

Microglial function and AD pathology. Microglia are present throughout the brain and their distribution varies by region. They have different shapes that reflect their essential functions of maintaining cerebral homeostasis and defense. Ramified microglia are the most common type in the healthy brain. They use branches to monitor the cerebral environment and detect injury signals. They then move their branches toward the damaged site and trigger a microglial response that involves reshaping synapses and keeping myelin stable. Microglia become highly ramified and have a robust power to clear pathogens. The highly branched form of microglia can also transform into a less branched shape as a result of engulfing pathological items, such as Aβ and Tau proteins. Microglia become dystrophic and hyperinflammatory with aging and neurodegenerative disorders such as AD. Moreover, the morphology of microglia varies in different regions and stages of the diseased brain. The temporal changes of the microglia aspect could depend on the intensity and duration of exposure to the harmful environment but could also be attributed to the divergent reaction of microglia to differing substances like Aβ or tau. AD, Alzheimer’s disease; Aβ, amyloid beta; PAMPs, Pathogen-associated molecular patterns

Fig. 3

Exercise for neuroinflammation and AD. Physical exercise can exert multiple positive effects on the brain of AD, such as enhancing cerebral blood flow, neurogenesis, synaptic plasticity, neurotrophic factors, antioxidant defense, and cognitive function. Exercise can inhibit the formation and deposition of Aβ and abnormal phosphorylation of Tau, partly by affecting α- and γ-secretase activity, BDNF production, and BACE1 function. More importantly, physical exercise can modulate neuroinflammation by directly and indirectly mediating the immune response of the CNS. Physical exercise can impact the activation state and phenotype of microglia and astrocytes in AD, resulting in the shift of the polarization of microglia and astrocytes from a pro-inflammatory (M1 or A1) to an anti-inflammatory (M2 or A2) pattern. This immune action results in reduced production of pro-inflammatory cytokines and enhanced production of anti-inflammatory molecules. Furthermore, physical exercise can suppress the activation of inflammasomes, such as NLRP3, which in turn decreases the production of IL-1β and caspase-1. Additionally, physical exercise can strengthen the thigh connection of the BBB, which can prevent the infiltration of peripheral immune cells and inflammatory molecules into the brain. AD, Alzheimer’s disease; Aβ, amyloid beta; BACE1, beta site APP cleaving enzyme 1

Fig. 4

Exercise mimetics for improvement neuroinflammation and AD. The neuroprotective effects of exercise are regulated by a variety of molecular factors that can be activated in a way similar to exercise through the administration of exercise mimetics. These mimetics have been shown to be effective in reducing neuroinflammation and managing AD pathology, making them a valuable alternative for patients who are unable to follow regular physical activity. Exercise benefits the brain through communication between peripheral organs and the brain, such as muscle–brain crosstalk, liver–brain crosstalk, and gut–brain crosstalk. Exercise increases the secretion of FNDC5/irisin from muscles, which can reduce oxidative stress and alleviate neuroinflammation in AD. The liver also generates important factors such as Gpld1 and SAM that are crucial for metabolism and neuroinflammation and can cross the BBB to affect brain function in various AD models. Progress in understanding the molecular mechanisms underlying these interactions endows patients to better utilize the power of exercise mimetics to improve health outcomes. AD, Alzheimer’s disease; BBB, blood–brain barrier; FNDC5, fibronectin type III domain-containing protein 5; Gpld1, glycosylphosphatidylinositol-specific phospholipase D1; SAM, S-adenosylmethionine