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. 2024 Jul 10;20(6):1555–1564. doi: 10.4103/NRR.NRR-D-24-00098

Therapeutic potential of exercise-hormone irisin in Alzheimer’s disease

Eunhee Kim 1,2, Rudolph E Tanzi 1,2, Se Hoon Choi 1,2,*
PMCID: PMC11688551  PMID: 38993140

Abstract

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer’s disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer’s disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer’s disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5’s protective roles and mechanisms against Alzheimer’s disease.

Keywords: Alzheimer’s disease, exercise, fibronectin type III domain-containing protein 5 (FNDC5), irisin

Introduction

Alzheimer’s disease (AD) is the most prevalent form of dementia associated with aging, clinically manifested by a gradual decline in memory and severe cognitive impairment. Neuropathologically, AD patients exhibit the presence of amyloid plaques, neurofibrillary tangles, and neuroinflammation in their brains. Amyloid plaques primarily consist of the amyloid-β protein (Aβ), which is released from the amyloid precursor protein (APP) through sequential cleavage by β- and γ-secretase. Neurofibrillary tangles are characterized by filamentous accumulations of aggregated hyperphosphorylated tau (pTau). Neuroinflammation responses, consisting of activated glial cells and pro-inflammatory cytokines secreted from them, correlate with the extent of brain atrophy and cognitive decline, leading to dementia. Despite best efforts, current therapeutic approaches have not produced fully effective therapies to fight against AD.

Importantly, physical exercise has been shown to be neuroprotective in AD in human and animal studies (Friedland et al., 2001; Adlard et al., 2005; Lazarov et al., 2005; Nichol et al., 2008; Belarbi et al., 2011; Choi et al., 2018). However, the underlying mechanisms by which exercise provides benefits against the disease are yet to be fully determined.

Irisin, cleaved and circulating from its precursor protein fibronectin type III domain-containing protein 5 (FNDC5), is a myokine produced by skeletal muscle during exercise in both humans and mice (Bostrom et al., 2012). Irisin is also expressed in the brain. Emerging evidence has shown that irisin/FNDC5 plays critical roles in neuroprotection in AD (Lourenco et al., 2019; Islam et al., 2021; Kim et al., 2023). In this review, we outline the functional roles of irisin/FNDC5 and its mechanisms in mediating the benefits of exercise in reducing the risk for AD. From a therapeutic perspective, given the challenges with physical activity for older adults, it is critical to identify exercise-induced secreted factors that mimic exercise benefits in the AD brain, dissect the distinct cellular responses elicited by target cells in the brain, and develop potential exercise mimetics.

Search Strategy

A search of the PubMed database (pubmed.ncbi.nlm.nih.gov) and Google Scholar was performed using the keywords as follows: “irisin AND (Alzheimer’s disease OR exercise OR amyloid beta OR tau OR dementia OR integrin OR inflammation OR heat shock protein 90).”

Effects of Physical Exercise on Alzheimer’s Disease

Favorable lifestyle and behavioral changes such as regular exercise significantly reduce the risk of the majority of AD cases (Norton et al., 2014). Human epidemiological and experimental studies suggest that higher levels of physical activity are associated with reduced risks of cognitive impairment, AD, and dementia as well as increased hippocampal volume (Laurin et al., 2001; Erickson et al., 2011; Buchman et al., 2012; Jia et al., 2019b). Greater physical activity also correlates with less microglial activation (Casaletto et al., 2022). Furthermore, physical inactivity in midlife is identified as a critical modifiable risk factor for AD development (Friedland et al., 2001). The benefits of exercise have become more evident in animal models as exercise counteracts various aspects of AD pathology: it reduces Aβ levels and amyloid deposition in the brain (Adlard et al., 2005; Lazarov et al., 2005); it reduces the levels of pTau (Leem et al., 2009; Belarbi et al., 2011); it increases neurogenesis in the hippocampus (Choi et al., 2018); it ameliorates cognitive dysfunction (Adlard et al., 2005; Belarbi et al., 2011; Choi et al., 2018); and it attenuates neuroinflammation, such as reactivity of astrocytes as reflected by reduction in glial fibrillary acidic protein (GFAP), release of pro-inflammatory cytokines (e.g., interleukin [IL]-1β, IL-6, and tumor necrosis factor alpha) and pro-inflammatory enzyme cyclooxygenase-2, as well as activation of extracellular signal-regulated kinase (ERK) (Nichol et al., 2008; Leem et al., 2011; Cardoso et al., 2017; He et al., 2017; Zhang et al., 2018; Li et al., 2020).

Exerkines, signaling moieties released by various tissues such as the muscle and liver during exercise, serve as vital messengers facilitating communication to the brain. Interestingly, systemic blood plasma administration has been shown to transfer the beneficial effects of exercise. Intravenous injection of plasma from exercised aged mice resulted in increased plasma concentrations of glycosylphosphatidylinositol–specific phospholipase D1, a glycosylphosphatidylinositol-degrading enzyme derived from the liver, leading to increased hippocampal levels of brain-derived neurotrophic factor (BDNF) as well as amelioration of age-related cognitive and neurogenesis impairment in sedentary aged mice (Horowitz et al., 2020). Clusterin, also primarily synthesized by hepatocytes, has been identified as a mediator of the beneficial effects of exercise on memory enhancement and reduction of brain inflammation (De Miguel et al., 2021). Nevertheless, the precise mechanisms and exact contributions of exerkines to AD pathology remain unclear.

Exercise-Induced Hormone, Irisin, in the Brain

Irisin is a 112-amino acid peptide that is proteolytically cleaved from FNDC5 composed of 209 amino acid residues and that is conserved between humans and mice (Figure 1). FNDC5 is a membrane-bound protein known to be expressed in muscle, adipose tissues, and brain (Bostrom et al., 2012; Wrann et al., 2013). FNDC5 has an N-terminal signal sequence, a fibronectin III domain (the primary part of irisin), a hydrophobic transmembrane region, and a C-terminal cytoplasmic tail. Through the N-terminal signal sequence, FNDC5 is directed to the endoplasmic reticulum where it is glycosylated. Glycosylation is associated with the cleavage of FNDC5 by a disintegrin and metallopeptidase domain (ADAM) family proteins such as ADAM10 (Yu et al., 2019).

Figure 1.

Figure 1

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Neuroprotective effects of exercise-induced irisin in AD brain.

During exercise, the PGC1α-dependent myokine, FNDC5, undergoes cleavage into irisin and is subsequently secreted from muscle. The extracellular chaperone Hsp90 serves as the activating factor that facilitates the “opening” of the integrin αV/β5 receptor, which enables high-affinity binding of irisin. In the AD brain, irisin was found to reduce amyloid and tau pathologies, mitigate neuroinflammation, and consequently enhance cognitive function. Created with BioRender.com. Aβ: Amyloid-β; APOE: apolipoprotein E; APPswe/PS1ΔE9 or PS1M146L: double transgenic mouse model overexpressing amyloid precursor protein (APP) Swedish and presenilin 1 (PS1) ΔE9 or M146L mutations; C3: complement C3; ERK: extracellular signal-regulated kinase; FNDC5: fibronectin type III domain-containing protein 5; GFAP: glial fibrillary acidic protein; Hsp90α: heat shock protein 90α; hTau: transgenic mouse model overexpressing human tau; IL-6: interleukin-6; LTP: long-term potentiation; NF-κB p65: nuclear factor kappa B p65; Pgc1α: peroxisome proliferator-activated receptor-gamma coactivator 1-alpha; pTau: phosphorylated tau; Ser: serine; STAT3: signal transducer and activator of transcription 3; TNFα: tumor necrosis factor alpha; 3D-AD: three-dimensional cell culture model of Alzheimer’s disease; 5×FAD: transgenic mouse model overexpressing familial Alzheimer’s disease mutations.

Irisin was initially found to promote the “browning” of mature white adipocytes in response to exercise (Bostrom et al., 2012). Physical exercise has been shown to induce the levels of irisin in both humans and mice. Ten weeks of endurance exercise (aerobic training) led to a 2-fold elevation in plasma irisin levels in healthy adult male subjects, compared to a non-exercised state (Bostrom et al., 2012). Jedrychowski et al. (2015) further detected and quantified the circulating irisin levels in plasma samples collected from young healthy male subjects following 12 weeks of high-intensity aerobic training using tandem mass spectrometry (Jedrychowski et al., 2015). They found that irisin circulates at approximately 3.6 ng/mL in sedentary individuals and its levels significantly increase to approximately 4.3 ng/mL by exercise. A “transient increase” in plasma irisin concentration occurs during the first hour of prolonged aerobic exercise, and this increase is subsequently diminished during the following recovery period (Kraemer et al., 2014). It has been shown that, in healthy young adults in their twenties, resistance exercise (a combination of exercises including chest press, lat-pull down, leg press, knee extension, seated rowing, shoulder press, arm curl, and triceps press down) also induces irisin response (Huh et al., 2015; Tsuchiya et al., 2015). Exercise appears to still induce irisin secretion in elderly individuals; Zhao et al. (2017) found that 12-week resistance exercise induces approximately 2-fold increase of plasma irisin levels in old male adults with a mean age of 62.1 years. The extent to which irisin is released may depend on exercise intensity. Comparing high-intensity exercise to low- or moderate-intensity exercise, studies generally report an enhanced irisin response with higher exercise intensities in healthy adult participants across age, sex, and fitness levels (Daskalopoulou et al., 2014; Huh et al., 2014; Tsuchiya et al., 2014; Tsai et al., 2021).

In 12-week-old wild-type mice, 3 weeks of free-wheel running, followed by 12 hours rest, led to an approximately 3-fold increase in Fndc5 mRNA levels in skeletal muscle and serum irisin levels, in a Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (Pgc1α, a transcriptional coactivator which regulates the genes involved in energy metabolism)-dependent manner (Bostrom et al., 2012). Thirty days of free-wheel running exercise also induced hippocampal Fndc5 gene expression in 6-week-old male wild-type mice (Wrann et al., 2013).

We currently do not know how much and/or what types of exercise produce enough irisin to be protective and which cell types in the brain are responsible for increases of irisin after exercise. The effectiveness of exercise in inducing irisin secretion in AD patients or older adults with mild cognitive impairment needs to be determined. This might be affected by several factors such as the severity of the disease, the type and intensity of exercise, and individual differences in irisin metabolism, requiring further investigation. It has been shown that obesity alters irisin concentration (Jia et al., 2019a; Makiel et al., 2023), which might also cause a different response to irisin levels during exercise.

Reduced Irisin/FNDC5 Levels in Alzheimer’s Disease

Lourenco et al. (2019) found that irisin level is significantly reduced in the hippocampus and cerebrospinal fluid (CSF) of AD patients, compared with cognitively intact individuals. While plasma irisin level was not altered in AD patients, their CSF/plasma irisin ratio was reduced. In the study of Islam et al. (2021), RNA sequencing data from the Mount Sinai School of Medicine and Mayo study revealed a notable decrease in Fndc5 expression, particularly in the parahippocampal gyrus, in AD patients compared to cognitively intact individuals.

Importantly, growing evidence supports the correlation of irisin levels with cognitive function, as well as with amyloid and tau pathologies, in studies involving humans and mice. CSF irisin correlates positively with Mini-Mental State Exam scores of both AD patients and control subjects (Lourenco et al., 2020; Goncalves et al., 2023). In patients with vascular dementia, there was a significant reduction in the serum irisin levels which was correlated with Montreal Cognitive Assessment score (Zhang et al., 2021). In another study, while hippocampal Fndc5 mRNA levels were not altered across Consortium to Establish a Registry for Alzheimer’s Disease staging of amyloid pathology, there was a trend of negative correlation between FNDC5 z-scores and both brain Aβ42 level and brain Aβ42/Aβ40 ratio (Lourenco et al., 2022). Furthermore, an association between the FNDC5 rs1746661 single nucleotide and cerebral Aβ levels was identified; cognitively impaired rs1746661(T) carriers had significantly higher Aβ positron emission tomography load than cognitively impaired non-carriers, with no change in CSF Aβ42 levels (Lima-Filho et al., 2023).

Furthermore, Fndc5 mRNA levels showed a trend of decrease in the hippocampus of human subjects with high tau pathology (at Braak stages 3–6) (Lourenco et al., 2022). There was a significant, negative correlation between Fndc5 mRNA and AT8 (pTau at Ser202/Thr205) immunoreactivity as well as a trend of the inverse relationship of Fndc5 mRNA with pTau at Thr181 (Lourenco et al., 2022).

Consistent with human studies, reduced expression of irisin/FNDC5 has been reported in AD transgenic APPswe/PS1ΔE9 mice which exhibit significant Aβ production and plaque formation as well as cognitive deficits through expression of familial AD (FAD)-associated APP Swedish (K670N/M671L) and presenilin 1 (PS1) ΔE9 mutations. FNDC5 protein expression was reduced in the hippocampus of 13- to 16-month-old APPswe/PS1ΔE9 mice compared to wild-type mice (Lourenco et al., 2019). Hippocampal Fndc5 mRNA expression was also reduced in 6-month-old APPswe/PS1ΔE9 mice (Islam et al., 2021). While it is not clear how irisin is reduced in AD mice, it has been shown that intracerebroventricular infusion of Aβ oligomers in wild-type mice and treatment of Aβ oligomers in primary rat hippocampal neurons led to a rapid reduction in FNDC5 expression (Lourenco et al., 2019), suggesting that Aβ species cause the irisin/FNDC5 reduction in AD. Further studies are required to assess the impact of pathological tau accumulation on the expression of irisin/FNDC5.

Metabolic dysfunction, including obesity and diabetes, has been linked to an increased risk of developing AD. A study involving human subjects reported a trend of reduced serum irisin levels in the obesity group with a first-degree family history of AD compared to the non-obesity group with the family history of AD (Tsai and Pai, 2021). Intracerebroventricular (ICV) injection of streptozotocin, commonly used to induce systemic diabetes, has been shown to cause cognitive impairment and elevate soluble Aβ42 levels in mice, accompanied by reduced hippocampal irisin levels as well as a negative correlation between hippocampal irisin and soluble Aβ42 levels (Hegazy et al., 2022). Decreased levels of irisin may be a contributing factor in how metabolic dysfunction influences the progression of AD.

Benefits of Irisin/FNDC5 on Cognitive Function

Downregulation of brain or peripheral FNDC5 by ICV injection of lentiviral shRNA that knockdown Fndc5 gene or by intraperitoneal administration of an anti-FNDC5 antibody, respectively, caused significant deficits in object recognition memory, accompanied by impaired synaptic plasticity in wild-type mice (Lourenco et al., 2019). Genetic deletion of Fndc5 (FNDC5 knockout mice) also led to cognitive impairment in the novel object recognition task in aged (21–24 months old), but not young (8–10 weeks old), mice (Islam et al., 2021). Interestingly, FNDC5 knockout mice failed to show exercise-induced improvements in learning and memory in the Morris water maze (Islam et al., 2021). While pattern separation, the ability to discriminate among similar experiences, was impaired in FNDC5 knockout mice, increasing FNDC5 expression by injecting AAV8-irisin into the dentate gyrus of the hippocampus rescued the memory impairment in these mice (Islam et al., 2021). Increased plasma irisin levels by treadmill running were correlated with improved working memory in physically inactive wild-type mice obtained by limiting their living space compared to that of a standard cage which led to deficits in working memory in the Y-maze (Park et al., 2022). Administration of an irisin-neutralizing antibody compromised the beneficial effects of exercise on the activation of the PGC1α/FNDC5/BDNF pathway (Park et al., 2022). Collectively, these results suggest that irisin/FNDC5 plays a critical role in cognitive functions under physiological conditions and upon exercise.

In AD, ICV injection of an adenoviral vector that overexpresses FNDC5 reversed memory impairment in radial arm water maze and contextual fear conditioning tasks in both APPswe/PS1ΔE9 and APPswe/PS1M146L mice (Lourenco et al., 2019; Figure 1). Peripheral injection of adeno-associated virus (AAV) 8-irisin improved cognitive function of APPswe/PS1ΔE9 mice in Barnes maze and of APPswe/PS1ΔE9 and 5×FAD mice in Morris water maze (Islam et al., 2021; Figure 1). The latter study suggests that irisin is an active moiety that benefits cognitive function in AD. Intraperitoneal administration of the anti-FNDC5 antibody abolished the protective effects of exercise against the defects in synaptic plasticity and memory both in wild-type mice infused with Aβ oligomers and in APPswe/PS1ΔE9 mice (Lourenco et al., 2019). These reports suggest that increasing irisin expression can ameliorate cognitive dysfunction in AD and that irisin mediates the exercise effects on cognitive improvement in AD. Although the mechanisms by which irisin ameliorates cognitive dysfunction in AD mice are not fully understood, Lourenco et al. (2019) showed that FNDC5 overexpression rescued impaired long-term potentiation in APPswe/PS1ΔE9 and APPswe/PS1M146L mice (Figure 1).

Impact of Irisin on Amyloid and Tau Pathologies

Lourenco et al. (2019) and Islam et al. (2021) tested the effects of irisin/FNDC5 on Aβ levels using animal models. Lourenco et al. (2019) found that ICV injection of an adenoviral vector that overexpresses FNDC5 significantly reduces soluble Aβ42, but not insoluble Aβ42, in the hippocampus, but not in the cortex, of 3- to 4-month-old APPswe/PS1M146L mice which express FAD-associated APP Swedish (K670N/M671L) and PS1 M146L mutations (both males and females were used; Table 1). Islam et al. (2021) showed that peripheral injection of AAV8-irisin did not change Aβ40 and Aβ42 levels in the cortex of 7-month-old male APPswe/PS1ΔE9 mice. However, this study did not assess its impact on soluble Aβ levels in the hippocampus nor on insoluble Aβ levels, necessitating further in vivo testing in the future (Table 1; Islam et al., 2021). Loss of FNDC5 significantly increased soluble Aβ40 levels in the cortex, but not in the hippocampus, of 6-month-old male APPswe/PS1ΔE9 mice (Islam et al., 2021).

Table 1.

Effects of irisin on Aβ and tau pathologies, as well as neuroinflammation in vivo

Model Aβ pathology Tau pathology Neuroinflammation Sex difference Reference
APPswe/PS1M146L mice which received ICV injection of an adenoviral vector overexpressing FNDC5 • Soluble Aβ42 is significantly reduced in the hippocampus, but not in cortex.
• Insoluble Aβ42 is not significantly reduced in the hippocampus (P = 0.06) and in cortex.		 Not studied Both male and female mice were employed. Sex difference was not reported. Lourenco et al., 2019
APPswe/PS1ΔE9 mice injected with AAV8-irisin via tail vein • No change in soluble Aβ40 and Aβ42 in the cortex.
• Soluble Aβ levels in the hippocampus and insoluble Aβ levels in the brain were not measured.
• No change in Aβ plaque burden in the cortex and hippocampus.		 Glial activation is reduced. Only male mice were used. Islam et al., 2021
hTau mice IP injected with recombinant human irisin protein pTau (Ser202) is significantly reduced in the hippocampus. TNFα is significantly reduced in the serum and hippocampus. pTau and TNFα reduction were observed only in female mice, but not in male mice. Bretland et al., 2021
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AAV8: Adeno-associated virus serotype 8; APPswe/PS1ΔE9 or PS1M146L: double transgenic mouse model overexpressing amyloid precursor protein Swedish and presenilin 1 ΔE9 or M146L mutations; Aβ: amyloid-β; FNDC5: fibronectin type III domain-containing protein 5; hTau: transgenic mouse model overexpressing human tau; ICV: intracerebroventricular; IP: intraperitoneal; pTau: phosphorylated tau; Ser: serine; TNFα: tumor necrosis factor alpha.

In an in vitro study, Aβ40 and Aβ42 levels were significantly reduced in the conditioned media of human embryonic kidney 293 cells transfected with FNDC5 plasmids (Noda et al., 2018). Furthermore, treatment of recombinant irisin protein reduces the binding of Aβ oligomers to rat hippocampal neurons, as determined by immunostaining with Aβ oligomers–sensitive antibody NU4 (Lourenco et al., 2019). While it has been shown that FNDC5 binds to APP and that 16 amino acids in the N-terminal sequence of APP C-terminus fragment C99 play a crucial role in this interaction in human embryonic kidney 293 cells (Noda et al., 2018), no direct binding between Aβ and FNDC5 was reported in rat hippocampal neurons (Lourenco et al., 2019).

We previously developed a three-dimensional (3D) cell culture model of AD from human neural stem cells that were genetically modified within a 3D cell culture system (referred as 3D-AD cultures; Choi et al., 2014; Kwak et al., 2020). This unique 3D-AD culture model successfully recapitulates the major events of the AD pathogenic cascade, including Aβ and tau pathologies. Using the 3D-AD cultures, we recently found that irisin treatment significantly reduces the levels of Aβ by increasing the activity/levels of neprilysin (NEP), an Aβ degrading enzyme, secreted from astrocytes (Figure 1; Kim et al., 2023). The ability of irisin to decrease Aβ42 levels in 3D-AD cultures was abolished when irisin was co-treated with sacubitril, a NEP inhibitor, implying that increased NEP activity is essential for irisin to lower Aβ levels. Irisin-induced NEP activity/level was also confirmed in human induced pluripotent stem cell-derived astrocyte cultures (Kim et al., 2023). Irisin treatment also reduced the level of dystrophic neurites and cell hyperexcitability, which are known to be associated with Aβ and/or tau pathologies (Figure 1; Kim et al., 2023).

However, irisin did not affect the activity/levels of another Aβ degrading enzyme, insulin-degrading enzyme (Kim et al., 2023). Irisin treatment also did not change the levels of full-length and C-terminal fragments of APP, suggesting that irisin does not affect APP processing or Aβ generation (Kim et al., 2023).

hTau mice exhibit age-associated tau pathology, including tau hyperphosphorylation and accumulation of neurofibrillary tangles, due to the expression of human microtubule-associated protein tau (MAPT). Intraperitoneal injections of irisin protein (0.1 mg/kg, 4 weekly injections across one month) reduce pTau (Ser202) levels in the hippocampus of pre-symptomatic female hTau mice, but not in male mice (Figure 1 and Table 1; Bretland et al., 2021). This study provides evidence that enhancing irisin may alleviate tau pathology in AD. We also observed that irisin treatment reduced sarkosyl-soluble and -insoluble pTau (Ser396/Ser404) levels in 3D-AD cultures, but there was no change in pTau/total tau ratio, mainly attributed to the trend of reduced total tau levels following irisin treatment (Kim et al., 2023).

Collectively, these in vivo and in vitro findings strongly support the consideration and development of irisin for both preventing and treating AD. Further studies will be required to check sex/brain region-specific effects of irisin, and if such effects exist, to reveal the mechanisms. Other unresolved questions include (1) whether the effects of irisin on Aβ reduction might involve factors beyond NEP upregulation and (2) whether reduced tau hyperphosphorylation by irisin treatment in the 3D-AD cultures is primarily attributable to Aβ reduction or if there exists an Aβ-independent mechanism contributing to the irisin-induced mitigation of tau pathology (Figure 1). Irisin reduced pTau levels in hTau mice which do not exhibit Aβ pathology (Bretland et al., 2021). This finding suggests that irisin might be able to reduce pTau through a mechanism independent of Aβ, which warrants further exploration of its mechanisms. If irisin affects tau pathology through astrocytes as it does to reduce Aβ levels, studies will be also necessary to determine the mechanism(s) by which astrocytes regulate tau pathology in neurons.

Anti-Inflammatory Action of Irisin

Hypertrophic reactivity of astrocytes is highly associated and dependent on the extracellular accumulation of Aβ as demonstrated by more pronounced transcriptional changes in astrocytes in proximity to amyloid plaques compared to those situated farther away in APPswe/PS1ΔE9 mice (Orre et al., 2014). Of note, there is growing evidence that irisin significantly exerts an anti-inflammatory action not only in adipocytes (Mazur-Bialy et al., 2017) and hepatocytes (Park et al., 2015) but also in the brain (Wang et al., 2018, 2019; Islam et al., 2021; Kim et al., 2023). While irisin, at the doses of 5 and 10 nM, failed to reduce Aβ-induced cell death in primary neurons, Aβ-induced cell death was attenuated in hippocampal neurons incubated with astrocyte-conditioned medium from mouse primary hippocampal astrocytes treated with irisin (Wang et al., 2018). We also found that irisin treatment significantly downregulates GFAP expression and pro-inflammatory cytokine IL-6 in the 3D-AD cultures (Figure 1; Kim et al., 2023). Irisin also attenuated reactive astrocyte gene and protein expression, such as nuclear factor kappa B p65 (NF-κB p65), complement C3, signal transducer and activator of transcription 3 (STAT3), and S100β (Figure 1). Apolipoprotein E was reported to be upregulated in both astrocytes with high GFAP expression and AD-associated astrocyte population (called disease-associated astrocytes) compared to astrocytes with low GFAP expression (Habib et al., 2020). Vimentin is an intermediate filament protein induced in reactive astrocytes and is identified as a marker for astrocytes associated with AD (Habib et al., 2020). We found that irisin reduces gene expression of Apoe and Vimentin in 3D-AD cultures (Figure 1; Kim et al., 2023). Interestingly, irisin, at the dose that did not reduce Aβ levels, significantly reduced GFAP expression and IL-6 level, suggesting that the observed decline in astrocyte reactivity is not attributable to the secondary effects of Aβ reduction (Figure 1; Kim et al., 2023).

Astroglial ERK activation and IL-6 upregulation are both early events in the pathogenesis of AD (Heyser et al., 1997; Webster et al., 2006). In AD patients, nearly 60% of GFAP-positive astrocytes in the prefrontal cortex were found to be positive for complement C3 (a marker for neurotoxic A1 astrocytes), suggesting that neurotoxic A1 astrocytes make up a large proportion of astrocytes in the prefrontal cortex and caudate nucleus that are affected by neurodegeneration in AD (Liddelow et al., 2017). In a previous study, we found that the irisin’s ability to reduce Aβ levels by NEP is mediated by the downregulation of ERK-STAT3 signaling (Kim et al., 2023). Blocking ERK and STAT3 signaling increased the levels of secreted NEP, leading to reduced Aβ40 and Aβ42 levels in 3D-AD cultures (Kim et al., 2023). Consistent with this finding, it has been shown that STAT3 knockout specifically in astrocytes in APPswe/PS1ΔE9 mice increased NEP protein levels (Reichenbach et al., 2019). It is crucial to investigate whether the reduction in neuroinflammation, stemming from inhibition of ERK-STAT3 signaling or other downstream targets within the ERK-STAT3 pathway, serves as a pivotal mechanism for NEP-induced Aβ clearance during irisin treatment (Figure 1).

Our 3D-AD cultures consist of neurons and astrocytes, but lack microglia (Kwak et al., 2020; Kim et al., 2023). Therefore, our data suggest that irisin mitigates inflammation through the attenuation of astrocyte reactivity. In line with our findings, irisin treatment attenuated the release of IL-6 and decreased the expression levels of cyclooxygenase-2 and NF-κB p65, both of which are upregulated in reactive astrocytes as pro-inflammatory factors (Hirst et al., 1999; Wu et al., 2009), in mouse primary astrocyte cultures exposed to Aβ25–35 (Wang et al., 2018). Consistent with our findings in the 3D-AD cultures, peripheral injection of AAV8-irisin significantly reduced glial activation in the brains of 7-month-old APPswe/PS1ΔE9 mice (Table 1; Islam et al., 2021). Intraperitoneal injections of irisin also reduced tumor necrosis factor alpha levels in the serum and hippocampus of female hTau mice (Figure 1 and Table 1; Bretland et al., 2021).

The anti-inflammatory action of irisin was also observed in streptozotocin-induced diabetic mice (Wang et al., 2019). Peripheral delivery of irisin recombinant protein (0.5 mg/kg, daily intraperitoneal injections for 3 weeks) attenuated the upregulation of GFAP, phosphorylated active forms of p38 mitogen-activated protein kinases, and STAT3 in the hippocampus of streptozotocin-induced diabetic mice, accompanied by amelioration of cognitive impairment (Wang et al., 2019).

Microglia are resident macrophages of the mammalian central nervous system. It has been reported that irisin decreases pro-inflammatory M1 polarization and stimulates macrophage polarization to anti-inflammatory M2 phenotypes in peritoneal macrophages activated by lipopolysaccharide (Dong et al., 2016; Xiong et al., 2018) and microglia in response to acute brain injury (Wang et al., 2022). Microglia also contributes to Aβ clearance via enzymatic degradation by expression of Aβ degrading enzymes and/or Aβ uptake/phagocytosis. It is not conclusive whether microglia express receptors for irisin. Wang et al. and Islam et al. found that the integrin β5 subunit, which serves as the irisin receptor (see integrin αV/β5 as a receptor for irisin below), is expressed in microglia (Islam et al., 2021; Wang et al., 2022). However, Chen et al. (2020) found that integrin β5 is expressed in astrocytes, but not in microglia, of AD patients, while it is not expressed either in astrocytes or microglia in cognitively intact individuals. Exercise transforms adipose resident macrophages from a pro-inflammatory M1 state to an anti-inflammatory M2 state, reducing inflammation (Kawanishi et al., 2010). Thus, it is pertinent to uncover whether irisin affects microglial activation and its function in neurodegenerative diseases as well as whether irisin mediates the exercise effects on neuroinflammation targeting microglia.

Integrin αV/β5 as a Receptor for Irisin

Integrins are heterodimeric receptors composed of alpha (α) and beta (β) subunits. In humans, at least 18 types of α and 8 types of β subunits have been identified (Takada et al., 2007). Each association of α and β subunits possesses its own binding specificity and signaling properties (Takada et al., 2007). The integrin complex αV/β5 has been identified as an irisin receptor, first in osteocytes (Kim et al., 2018) and later in osteoclasts (Estell et al., 2020), adipose tissues (Oguri et al., 2020), and cardiomyocytes (Lin et al., 2021).

By mass spectrometry assays, we found that three integrin α subunits (αV, α6, and α7) and four β subunits (β1, β4, β5, and β8) are expressed in the 3D-AD cultures (Kim et al., 2023). Integrin αV is an exclusive binding partner of integrin β5 to form integrin αV/β5 subtype. Experiments in our 3D-AD cultures using L-a-aminoadipate, astrocyte-selective gliotoxin, to ablate astrocytes showed that integrin αV/β5 complex is exclusively expressed in astrocytes (Kim et al., 2023). Supporting this, in the central nervous system, the integrin β5 subunit has been shown to be highly expressed in astrocytes, thus used as an astrocyte-specific gene suitable for their isolation (Foo et al., 2011). Blocking integrin αV/β5 receptor pharmacologically by treating with an antagonistic integrin αV/β5 antibody or an integrin αV/β5 inhibitor or genetically by knocking down the integrin β5 expression abolished the effect of irisin on reducing Aβ levels from increased NEP release in the 3D-AD cultures (Kim et al., 2023). These results suggest that the integrin αV/β5 receptor functions as the irisin receptor on astrocytes, essential for the irisin-induced release of astrocytic NEP, which contributes to the clearance of Aβ and the reduction of gene expression associated with astrocyte reactivity (Figure 1; Kim et al., 2023).

Two-color direct stochastic optical reconstruction microscopy with single-molecule resolution (dSTORM) and Clus-DoC analyses also showed that the colocalization of irisin with integrin αV/β5 is greater than that with integrin αV/β3 in adult hippocampal primary neuronal stem cell cultures (Islam et al., 2021). Integrins interact with extracellular matrix proteins and actin skeleton in specialized sites known as focal adhesions (Takada et al., 2007). RNA sequencing analyses indicate that pathways related to focal adhesions are affected in both FNDC5 knockout mice and APPswe/PS1ΔE9 mice overexpressing irisin (Islam et al., 2021), supporting the interaction between irisin and integrins.

At rest, only about 0.1% of integrins exist in the open conformation, requiring activation for high-affinity ligand binding (Li et al., 2017). A et al. (2023) found that extracellular heat shock protein 90α (Hsp90α, stress-inducible form of Hsp90) interacts with integrin αV/β5 to allow irisin to then bind to integrin αV/β5 to activate irisin-induced signaling (Figure 1). The extracellular level of Hsp90α is induced both in the muscle extracellular fluid and plasma of mice, notably after a single intense bout of exercise, occurring within an hour (A et al., 2023). While the ability of Hsp90, as a large protein, to cross the blood–brain barrier (BBB) remains incompletely understood, levels of Hsp90 protein were found to increase in the brains of non-diabetic rats as well following 8 weeks of exercise training, but not in those of diabetic rats (Lappalainen et al., 2010).

It is still uncertain whether exercise can elevate Hsp90 levels in the AD brain, along with irisin secretion, similar to the induction of other heat shock proteins, such as Hsp70, by exercise and irisin (Dehghan et al., 2021). Aβ and tau are both substrates of Hsp90, which may prevent their aggregation (Evans et al., 2006; Schopf et al., 2017). Furthermore, Hsp90 inhibition in AD has been identified to confer neuroprotection through the activation of heat shock factor 1 (Wang et al., 2017), underscoring the multifaceted role of Hsp90 in AD pathology. There is no documented evidence regarding exercise-induced alterations in integrin β5 expression, whereas other integrin subtypes were found to be induced during exercise (Ding et al., 2006). Additional research is required to clarify the mechanistic relationships among irisin, exercise-induced alterations in Hsp90, and integrin expression in the context of AD pathology. This will deepen our understanding of whether and how alterations in irisin signaling may play a role in the progression of AD pathology.

Fibronectin type III 10th domain, similar in size to irisin, does not compete with irisin for binding at the integrin site (A et al., 2023). Hydrogen/deuterium exchange mass spectrometry revealed the sites covered by irisin are primarily on the integrin β5 subunit, distinct from RGD (Arg-Gly-Asp) binding sites in other αV integrins (A et al., 2023). There might be potential differences in downstream pathways between irisin- and other RGD-mediated integrin signaling. Given the significant affinity and response of integrin αV/β1 to irisin in bone cells (Kim et al., 2018), additional research is needed to explore whether additional integrin subtypes expressed in both neurons and astrocytes could serve as additional irisin receptors in AD and other neurodegenerative diseases.

Notably, inhibiting integrin αV/β5 alone decreases Aβ levels in 3D-AD cultures, without irisin treatment (Kim et al., 2023). While irisin reduced STAT3 signaling, inhibiting integrin αV/β5 receptor did not affect STAT3 levels in the 3D-AD cultures (Kim et al., 2023). There might be distinct mechanisms underlying Aβ reduction when blocking the integrin αV/β5 receptor from other ligands compared to activating it with irisin. During reactive astrogliosis, integrins are upregulated with altered extracellular matrix composition that controls astrocytic response to inflammation (Gaudet and Popovich, 2014; Lagos-Cabre et al., 2017). Indeed, the expression of integrin β5 and STAT3 is increased in the human AD brain, which was attenuated by exercise (Hill and Gammie, 2022). High integrin β5 expression was also associated with immune response, inflammatory response such as NF-κB pathway, and integrin-mediated signaling in glioblastoma (Zhang et al., 2019). As such, the functional roles of astroglial integrin β5 in AD pathogenesis should be further identified.

Conclusion and Perspectives

AD has become an increasing health burden. While the development of drugs for the disease has largely centered around targeting Aβ, it has not fully modified the disease progression. The associated side effects (e.g., brain hemorrhage) have also underscored the urgent need for more effective and safer alternatives. The neuroprotective effects of physical exercise on AD pathology have been well-established in both human and animal studies. However, the exact molecular mechanisms of the exercise-induced benefits in the brain, which should be diverse and complex, have not been well elucidated. Understanding the molecular mechanisms of exercise is critical for the development of exercise-based interventions and therapies, particularly for aged and AD patients who may face challenges in engaging in physical activity.

Among exerkines showing neuroprotective effects in the brain, irisin stands out as a promising therapeutic target for preventing and treating AD. Its potential benefits include reducing levels of Aβ and pTau as well as neuroinflammation, leading to improvement of cognitive function. Irisin appears to cross the BBB to affect brain function. Plasma irisin levels were found to be correlated with the ratio of CSF/plasma irisin in a nonlinear manner, suggesting that irisin might cross the BBB via a saturable transport system (Ruan et al., 2019). Since the integrin αV/β5 receptor is also expressed in endothelial cells (Bi et al., 2020), we cannot exclude the possibility that irisin crosses the BBB via a receptor-mediated active transport system. Administering FNDC5 peripherally using adenoviral vectors increases blood irisin levels and induces upregulation of the BDNF gene in the hippocampus of mice (Wrann et al., 2013). It has been shown that peripherally delivered AAV-irisin crosses the BBB in AD transgenic mice (Islam et al., 2021) and that peripherally injected recombinant irisin also crosses the BBB in wild-type mice (Kam et al., 2022). Although irisin did not show any toxicity in our 3D-AD cultures (Kim et al., 2023), the efficacy and toxicities of irisin should be determined in healthy humans and those with AD. Establishing the optimal therapeutic dose and time window in AD patients should also be crucial, as they will be critical for irisin’s therapeutic development. Further mechanistic studies are expected to elucidate the receptors and cell types in the brain responsible for the cognitive benefits associated with irisin. Moreover, there should be a critical need to discover and develop therapeutic analogs of irisin and to identify factors contributing to irisin tolerance and/or resistance. As such, there is a lot of potential for significant contributions to be made in this emerging area of AD research.

Funding Statement

Funding: This work was supported by Cure Alzheimer’s Fund (to RET and SHC), JPB Foundation (to RET), and R56AG072054 (to SHC).

Footnotes

Conflicts of interest: The authors declare no conflicts of interest.

C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y

Data availability statement:

Not applicable.

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