Introduction

Alzheimer´s disease (AD) is the most common neurodegenerative disease (EMA 2018). Six million Americans were living with AD in 2020 and it is expected that in 2050 we will have approximately 13.8 million people living with AD worldwide (Physicians 2020). AD is also a type of dementia where patients usually present difficulty forming new memories. The dementia has been clinically attributed to the cell death that results from a large number of insoluble amyloid fibrils. These amyloid fibrils may be present in a vast number of tissues (muscle, bones, etc.) and can cause damage to peripheral tissues and the brain (Gong et al. 2003). Aggregations of amyloid beta (Aβ) oligomers, strong central nervous system (CNS) neurotoxins, are thought to be responsible for cellular damage, and has been associated with the development of insulin resistance and cognitive decline in AD (Dias et al. 2020).

The main feature of type 2 diabetes (T2D) is also insulin resistance (De Sousa et al. 2021b). This chronic metabolic disorder affects over 200 million individuals globally, and it is projected that this may rise to 400 million individuals with diabetes by 2030 (IDF 2015). T2D is characterized by the presence of hyperglycemia and insulin resistance, with or without insulin deficiency (De Sousa et al. 2021b). The presence of cognitive decline in T2D is supported by a higher risk of developing neurodegenerative diseases (De Sousa et al. 2021e), especially AD (Wang et al. 2018a). Physical inactivity can contribute to the development of AD and/or T2D (Snel et al. 2012). For this reason, physical exercise is a non-pharmacological recommendation for patients with diabetes (De Sousa 2018; Ranasinghe et al. 2018), AD (Alkadhi and Dao 2018; De Sousa et al. 2021d), and many others pathological conditions (Pedersen and Saltin 2015; De Sousa et al. 2020b, 2021a; Eskandari et al. 2020; Cavalcante et al. 2021).

Aerobic exercise training (AET), a type of physical exercise, can induce marked physiological adaptations, such as increased production of Irisin (De Sousa et al. 2021c). AET can also regulate microRNAs (miRNAs), which play an important role in the regulation of signaling pathways that will interfere in different pathologies (Caria et al. 2018). Examining the effects of AET in AD and T2D may help to explain mechanisms of insulin resistance, inflammation and metabolic dysregulation in neurodegenerative disorders. A recent systematic review suggested that large-scale, robust controlled randomized clinical trials should be performed to evaluate if physical exercise would contribute to improve cognitive function in T2D patients (Zhao et al. 2018), what we could suggest also to be better addressed in AD. The identification of how AET influences the regulation of miRNAs in T2D and AD may also identify molecular targets for pharmacological interventions. Here, we have performed a narrative review to try to link some of these mechanisms. This study evaluated the potential novel effects of AET on AD and T2D.

Classic mechanisms of AD

AD is the most common cause of dementia and related neurodegenerative disorders (Alzheimer´s Association 2010). Aging is the greatest risk factor for AD, but the development of the pathophysiology is not a normal part of aging. The amyloid cascade hypothesis based on the role of Aβ peptide has been the major point investigated in the last 30 years (Folch et al. 2019). However, medicines developed that had as main target β-secretase 1 (BACE1), which is the major beta secretase for the generation of β-peptides, have failed in clinical trials (Hawkes 2017; Egan et al. 2018).

The amyloid hypothesis consists in the cleavage of amyloid precursor protein (APP) by β- and gamma-secretase what will lead to an increased number of cytotoxic residues, which will form oligomers that will cause neuron damage (De Sousa et al. 2020a). Inflammation, oxidative stress and insulin resistance can be also seen in the brain of AD patients and animal models (Zhao et al. 2004; Lee et al. 2009). Another hypothesis for the development of AD is Tau hyperphosphorylation (Gratuze et al. 2018). Synaptic dysfunction is related to accumulation of hyperphosphorylated tau protein in AD (Smith et al. 2015). The third mostly studied hypothesis in AD reveals the existence of cholinergic neurons loss and nicotinic acetylcholine receptors (nAChRs) reduction throughout the brain (Magdesian et al. 2005).

Nevertheless, all listed hypothesis can be found in AD patients and in animal models suggesting multiple harmful effects of this disease to the brain. However, it seems that insulin resistance, a common feature between AD and T2D, develops a pivotal role between Aβ and tau pathologies (Mullins et al. 2017; Rad et al. 2018).

Classic mechanisms of T2D

Several processes are associated with T2D and the main known mechanisms linked to this disease are: hyperglycemia, insulin resistance, hyperinsulinemia, hyperlipidemia, increase in reactive oxygen species, inflammation, fibrosis and apoptosis (Roden and Shulman 2019).

State of overnutrition generates metabolic imbalance, promoting activation of the renin–angiotensin–aldosterone system, which stimulates the mechanistic of rapamycin (mTOR)-S6 kinase 1 (S6K1), inhibiting insulin signaling on IRS-1 and IRS-2, decreasing the activation of via PI3K-AKT. Another described molecular mechanism that leads to the inactivation of the PI3K-AKT signaling pathway and insulin resistance is the phosphorylation of serine residues from IRS-1 or IRS-2 that attenuates glucose uptake by this signaling pathway (Jia et al. 2016).

These long-term metabolic and molecular changes will promote dysfunction of some cell organelles, such as: mitochondria, generating mitochondrial dysfunction; in the endoplasmic reticulum, leading to endoplasmic reticulum stress and impaired calcium handling (Jia et al. 2016); and in the cell nucleus and DNA, due to epigenetic alterations linked to changes in DNA methylation, histone acetylation and deacetylation (Kang et al. 2016), modified expression of miRNAs, long-non coding RNA, among many other non-coding RNAs (Raciti et al. 2015), resulting in remodeling and dysfunction of specific organs such as the brain (Biessels and Despa 2018), heart (Dillmann 2019), blood vessels (Shi and Vanhoutte 2017), adipose tissue (Roden and Shulman 2019), kidneys (Assayag et al. 2017) and gut (Hashimoto et al. 2020).

However, a simple session of aerobic exercise activates the AMP kinase, which in turn induces the translocation of GLUT4 to the cell surface, increasing glucose uptake (Musi et al. 2001), demonstrating that exercise is an important tool in combating insulin resistance, T2D and AD (Improta-Caria et al. 2020).

AET features

Physical exercise is considered an excellent non-pharmacological strategy to prevent and help treat AD (De la Rosa et al. 2020) and T2D (Sampath Kumar et al. 2019). AET more specifically is the type of exercise that is widely studied in the literature and shows several positive effects on the human body (Hillman et al. 2008). AET improves cell function of the innate and adaptive immune system (Improta-Caria et al. 2021), improves the function of endocrine hormones (Hackney and Lane 2015), promotes changes in the morphology and function of several organs, especially the brain (Colcombe et al. 2006), heart (Schüttler et al. 2019) and blood vessels (Hurley et al. 2019), which are very affected organs in both AD and T2D.

In recent years, the effects of AET on molecular mechanisms have been investigated, mainly mechanisms associated with miRNAs in both healthy (Baggish et al. 2011; Nielsen et al. 2014) and diseased individuals (Fernandes et al. 2012; Gomes et al. 2017; Improta-Caria and Aras 2021). However, the molecular mechanisms regulated by AET-induced miRNAs in AD and T2D are poorly studied.

MiRNAs: links between AET, T2D and AD

MiRNAs are small non-coding single-stranded RNAs, having usually 22 nucleotides, that play a role in post-transcriptional mechanisms of the regulation of gene expression (Ha and Kim 2014). MiRNAs are involved with obesity (Iacomino et al. 2016) and adipocyte differentiation and proliferation, and target PPAR´s during the process (Tyagi et al. 2019). They also influence cardiovascular inflammation (Nemecz et al. 2016), T2D (Baroukh et al. 2007), AD (Liu et al. 2014c), and AET (Silva et al. 2017). MiRNAs regulate up to 60% of the protein-coding genes in the human genome (Muljo et al. 2010). A portion of our genome generates functional small RNAs that will not be translated into protein, but that will instead play a very important role in regulating gene expression (Caria et al. 2018). Moreover, miRNA expression profiles are evidently able to identify different types of cancers, however the role of miRNAs in cell biology or organisms remains unclear. In order to understand the roles of miRNAs, it is necessary to systematically identify the targets they regulate.

Expression of miRNAs are associated with many pathophysiological mechanisms involved in T2D (insulin synthesis, insulin resistance, glucose intolerance, hyperglycemia, intracellular signaling, and lipid profile) (Caria et al. 2018). MiRNA regulation is related to several comorbidities and complications of T2D, such as impaired angiogenesis, micro- and macrovascular damage (Stępień et al. 2018). There is a strong possibility that miR-126 is involved in the pathogenesis of micro- and macrovascular complications of T2D (Caria et al. 2018). A number of miRNAs have been identified as regulators of insulin transcription and translation at higher levels of blood glucose, such as miR-124, miR-107, miR-30a, and miR-30d (Baroukh et al. 2007; Tang et al. 2009; Aaltonen et al. 2010). Downregulation of miR-484, miR-690, and miR-296 was observed in mice models of T2D, and is related to the inhibition of insulin transcription (Tang et al. 2009). Insulin secretion is also regulated by a few miRNAs, including miR-375 and miR-9 (Poy et al. 2004; Joglekar et al. 2009). The regulation of the molecular mechanisms involved in T2D patients seems to be regulated by mir375, miR-101 and miR-802 (Kong et al. 2011; Higuchi et al. 2015). These are a few examples only of how miRNAs are crucial in several pathophysiological roles in T2D and associated comorbidities and conditions (Table 1).

Table 1 Circulating miRNAs in T2D (Clinical studies)
Full size table

MiRNA dysregulation is also evident in AD and has been associated with several neuropathological alterations (Table 2), including altered expressions of species that are known to be involved in AD pathology, including microglia and astrocytes (Shaik et al. 2018). MiR-132/212 was reported to be down-regulated in the frontal cortex in mild cognitive decline (Smith et al. 2015). MiRNA 153 is also downregulated in the AD brain and it is associated with higher expressions and mutations of APP (Long et al. 2012). MiR-195 is suggested to be downregulated in the AD brain leading to increased production of Aβ40 and Aβ42, the strongest cytotoxic forms of the peptide, contributing to a greater formation of pathogenic amyloid plaques (Shaik et al. 2018). Future studies must investigate drugs that can target dysregulation of miRNAs in T2D and AD. Nevertheless, the investigation of alternative signaling pathways and mechanisms, including the changes induced in miRNAs by AET is necessary (Table 3). Identifying the changes caused by AET hold potential for the development of novel therapies for the treatment of T2D and AD.

Table 2 Circulating miRNAs in AD (clinical studies)
Full size table
Table 3 Circulating miRNAs in AET (response during and after exercise in clinical studies)
Full size table

AET induces changes in miRNAs in both T2D and AD

AET is capable of improving insulin resistance and dyslipidemia (De Sousa 2018). Cellular homeostasis is markedly affected by a single exercise session and in response to chronic exercise training, which induce marked changes in the circulating miRNA profile (Caria et al. 2018). AET promotes positive effects in miRNA-mediated gene regulation among healthy participants, but clinical studies focusing on people with T2D and AD have not been well-explored to date (Muljo et al. 2010; Caria et al. 2018; Shaik et al. 2018).

The identification of the miRNAs regulated by AET in people with T2D and/or AD is important in order to understand the molecular alterations in signaling pathways, proteins, enzymes and interleukins. These findings are crucial for the development of new therapies, drug-related or not, in order to prevent or combat TD2M and AD.

Circulating miRNAs overlaps between AD, T2D and AET

Here, we show what is currently known about identified circulating miRNAs in AD, T2D and AET, and the common miRNAs to all three on a Venn diagram (Fig. 1). We identified 7 circulating miRNAs deregulated and associated with AD and T2D, 76 circulating miRNAs deregulated in AD and AET and 11 circulating miRNAs deregulated in T2D and AET. In particular, we identified 26 circulating miRNAs deregulated in the 3 situations, they are: miR-532, let-7i, miR-144, miR-140, miR-30a, miR-375, miR-222, miR-30d, miR-125b, miR-126, miR-21, miR-142, miR-34a, miR-20b, miR-146a, miR-148a, miR-15a, miR-23a, miR-766, miR-210, miR-195, miR-130a, miR-424, miR-23b, miR-29a and miR-191. After an analysis of the expression pattern of these 26 miRNAs, it was found that 2 miRNAs (miR-23a and miR-532) showed an expression pattern different from the pattern in the AET. Both miR-23a and miR-532 are downregulated in disease and upregulated in AET.

Fig. 1
figure 1

Venn diagram representing overlaps of circulating miRNAs in AD, T2D AND AET. The Venn diagram depicts miRNAs that were identified and dysregulated in AD, T2D AND AET, and showing the overlaps in the three conditions

Full size image

Inflammation is a very common situation in AD and T2D and NF-κB is an overexpressed transcriptional factor in this situation. The NF-κB p-65 subunit binds to miR-23a promoter and decreases its expression (Rathore et al. 2012), favoring an increase in the inflammatory profile. Dysregulation of miR-23a has also been associated with dyslipidemia (Karolina et al. 2012). On the other hand, AET increases the expression of miR-23a, suggesting that AET can decrease the inflammatory process and attenuate dyslipidemia through the regulation of this miRNA in AD and T2D.

Under conditions of inflammation, miR-532 is downregulated and this miRNA targets the proapoptotic gene BCL2 antagonist/killer 1 (BAK1). Thus, BAK1 is overexpressed, elevating the inflammatory profile and promoting apoptosis (Chen et al. 2020). In contrast, AET increases miR-532 expression, suggesting that it may be a molecular mechanism induced by AET to reduce BAK1 expression and subsequently decrease inflammation and apoptosis in AD and T2D. These remarkable data are further strong evidence that scientific research should be driven to investigate the changes induced in miRNA´s by AET in T2D and AD. Such identification will also facilitate finding possible targets for new therapies.

Conclusions

AET is a non-pharmacological tool that can prevent and be used as a therapy in T2D and AD, helping to avoid memory loss and several pro-inflammatory mechanisms in both diseases. We suggest that investigating molecular mechanisms of the actions of AET on molecular pathways and the regulation of miRNAs will not only provide all known benefits of how better prescribe physical exercise, but will also illuminate new targets to the ultimate aim that is to find a cure to these diseases. AET will at the very least likely diminish the suffering of patients through the development of new and effective therapies. AET and physical exercise in general is a therapy itself.