Erythrocytes as Potential Link between Diabetes and Alzheimer’s Disease
- 1School of Medicine, Biochemistry and Clinical Biochemistry Institute, Università Cattolica del Sacro Cuore, Rome, Italy
- 2Human, Social and Health Department, University of Cassino and Lazio Meridionale, Cassino, Italy
Many studies support the existence of an association between type 2 diabetes (T2DM) and Alzheimer’s disease (AD). In AD, in addition to brain, a number of peripheral tissues and cells are affected, including red blood cell (RBC) and because there are currently no reliable diagnostic biomarkers of AD in the blood, a gradually increasing attention has been given to the study of RBC’s alterations. Recently it has been evidenced in diabetes, RBC alterations superimposable to the ones occurring in AD RBC. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of RBC’s alterations and vice versa. Once again this represents a further evidence of a shared pathway between AD and T2DM. The present review summarizes the two disorders, highlighting the role of RBC in the postulated common biochemical links, and suggests RBC as a possible target for clinical trials.
Patients affected by Alzheimer’s disease (AD) have senile plaques in central nervous system (CNS) areas where neurodegenerative process takes place (Selkoe, 1994). AD plaques are composed principally by amyloid β-peptide (Aβ), that can be formed by 39–43 amino acids and that derives from a longer precursor (APP) localized in transmembrane. Aβ, as showed by Yankner et al. (1990), is neurotoxic especially in aggregate form and it can lead to apoptosis of neuronal cells.
Although, historically, amyloid plaques were thought to cause AD (Hardy and Higgins, 1992), recent data suggest that Aβ oligomers, instead of plaques, trigger the pathological process (Roychaudhuri et al., 2009). On the basis, many studies have investigated the patho-mechanisms and to identify the risk factors of the disease. Vascular related diseases such as diabetes, hypertension and hypercholesterolemia have been reported to favor AD (Helzner et al., 2009) and in addition, AD patients have an increased risk of stroke events (Chi et al., 2013; Tolppanen et al., 2013). These data suggest a reciprocal relationship between vascular risk factors and AD.
It has been shown that Aβ causes oxidative stress (Nunomura et al., 2001). Beside its presence in CNS, Aβ can be detected in platelets (Chen et al., 1995) and blood (Seubert et al., 1992), where it interacts with red blood cells (RBC). Our previous studies (Clementi et al., 2004; Misiti et al., 2012; Carelli-Alinovi et al., 2015a, 2016a) suggest that Aβ is able to alter RBC metabolism. Other studies (Jayakumar et al., 2003; Mandal et al., 2003; Nakagawa et al., 2011; Lang and Lang, 2015), indicate that Aβ could impairs RBC functionality and integrity, enhancing abnormalities at the vascular level that could be responsible for AD (de la Torre, 2002). Aβ induces oxidative injury to RBC (Kay, 1984; Mandal et al., 2003; Clementi et al., 2007) that can lead to eryptosis (Nicolay et al., 2007). Diabetes is accompanied with impaired microcirculation resulting in relative tissue hypoxia (Ditzel and Standl, 1975; Ditzel et al., 1978). It induces numerous abnormalities in RBC, responsible for microcirculation impairment (Le Devehat et al., 1994), including increased aggregation (Schmid-Schönbein and Volger, 1976) and membrane viscosity (Baba et al., 1979) and decreased deformability (McMillan, 1975; Vague and Juhan, 1983). Reduced viscoelastic properties of RBC membranes have been attributed to the alterations in membrane lipid-protein interactions. RBC membrane is altered by free radicals-induced oxidative stress (Kumar, 2012). Diabetic altered RBC became able to adhere to endothelium by a specific interaction between advanced glycation end products (AGE) present on RBC and a specific receptor on the endothelium (Grossin et al., 2009). Once again, all this morphological, structural and biochemical changes result in an accelerated clearance of RBC. In the present review, we describe RBC main alterations in a diabetic milieu and in AD and refer to common pathophysiological mechanisms linking these two diseases.
Evidences for A Connection Between Type 2 Diabetes and Alzheimer’s Disease
Previous studies (Ott et al., 1999) show that AD is more frequent in type 2 diabetes (T2DM) patients. These findings indicate that glucose dysmetabolism is involved in AD onset. Glucose dysmetabolism occurs in brain regions during pre-symptomatic period, although further studies will be needed to clarify if glucose dysregulation starts AD pathology, or it is a secondary effect due to Aβ-related toxic events and tau formation (Sato and Morishita, 2015). Recent studies demonstrate that individuals with T2DM develop AD with high frequency (Ott et al., 1999; Crane et al., 2013; Huang et al., 2014), and patients with hyperglycemia are more prone to develop AD from mild cognitive impairment (MDI; Morris et al., 2014). In addition, T2DM-related conditions, including obesity (Beydoun et al., 2008), hyperinsulinemia (Peila et al., 2004) and metabolic syndrome, may be risk factors for AD.
In this regard, there are in literature data on impaired insulin action or production, impaired signaling pathway involving insulin receptor (IR) and insulin growth factor (IGF) defects, toxicity caused by hyperglycemia, increase of advance glycation end products, inflammation at the vascular level and others (Sjöholm and Nyström, 2006; Luchsinger, 2012; de la Monte, 2012). It has been found a reduction in neuronal insulin transport, uptake and concentration in animal studies (Baskin et al., 1985; Banks et al., 1997; Kaiyala et al., 2000).
Recently Takeda et al. (2010) reported that defects in insulin-like growth factor 1 (IGF-1) receptor, IR and insulin receptor substrate (IRS)-1/2, suggesting that these events could be involved in the mechanism underlying AD and diabetes. Insulin signaling impairment leads to loss of neuronal function, plaque formation and NTF formation (Biessels and Kappelle, 2005). Aβ is able to bind IR in a competitive way, inhibiting its auto-phosphorylation and downstream kinases necessary for neuronal function in hippocampal region (Townsend et al., 2007). It was shown that mice in hyperglycemic or hyperinsulinemic status have a higher ability to generate Aβ in brain (Ho et al., 2004; Cao et al., 2007). Moreover Zhang et al. (2012) showed that in APP/PS1 mice model, Aβ correlate with insulin resistance and in humans with hyper-glycemia. In particular, in hepatocytes, they showed that Aβ induces insulin resistance, triggering JAK2/STAT3/SOCS-1 signaling pathway. Furthermore, insulin could interfere with the proteolytic Aβ degradation, that is known to occur via a metalloprotease, that recognize as substrates, also insulin and IGF-1 (Gasparini et al., 2002; Carro and Torres-Aleman, 2004; Plum et al., 2005; Carro et al., 2006; Moloney et al., 2010). High plasma insulin levels, occurring in insulin resistance patients, may be responsible for insulin-degrading enzyme inhibition; this event, as reported by the authors, impairs Aβ degradation, favoring its toxicity (Gasparini et al., 2002; Carro and Torres-Aleman, 2004; Plum et al., 2005; Carro et al., 2006; Moloney et al., 2010). Insulin resistance promote tau phosphorylation, leading to glycogen synthase kinase-3β activation (Li et al., 2006; Kremer et al., 2011). Genetic factors are involved in diabetes and AD cognitive impairment such as apolipoprotein E (ApoE). For example, ApoEε4 allele is present in the “late onset familial” and the “sporadic” ones, both forms of AD (Corder et al., 1993). A previous study has shown synergistic effects between the ApoEε4 and diabetes for developing AD (Peila et al., 2002).
AD is promoted by a T2DM status and their linkage is furthermore influenced by many factors, including ethnicity, glycemia and insulin. Thus, it becomes important to understand which of these factors are more decisive in the correlation between AD and T2DM, considering that in literature there are several controversial data (Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), 2001; Petrovitch et al., 2001; Peila et al., 2002). In particular, Alzheimer-type pathology was found less frequent in diabetic patients when compared to non-diabetic subjects (Nelson et al., 2009).
Red Blood Cells in Type 2 Diabetes
Diabetes is characterized by microvascular alteration (Jones and Peterson, 1981) and in diabetic RBC have been observed several functional and structural alterations (Jones and Peterson, 1981), such as a reduced life span (Peterson et al., 1977; Pescarmona et al., 1982), excessive aggregation (Schmid-Schönbein and Volger, 1976; Satoh et al., 1984), altered membrane phospholipid asymmetry (Wali et al., 1988), and a higher tendency to adhere to endothelial cells (Wautier et al., 1981; Wali et al., 1988). RBC alterations are linked to glucose metabolic disorder, whereas, others are associated with diabetes-related dysfunctional mechanisms (Jain et al., 1983). The main important mechanisms that affect RBC structure and function in diabetes patients are given below.
RBC compared to other cells are more affected by oxidative damage occurring in diabetes (Beisswenger et al., 2005), because of its higher levels of iron and poly-unsatured fatty acids. High blood glucose concentration causes phosphatidylserine (PS) exposure, a marker of eryptosis, triggering RBC removal by macrophages (Boas et al., 1998; Eda and Sherman, 2002). Similarly, methylglyoxal inhibits ATP production and decreases GSH levels (Nicolay et al., 2006), resulting in PS exposure, and eventually in anemia and microcirculatory disequilibrium (Nicolay et al., 2006).
Lipids and its Modifications
Fatty acid composition changes in T2DM RBC. In particular, arachidonic acid and the total content of n-6 fatty acids were inversely proportional to the plasma insulin content during in fasting conditions (Clifton and Nestel, 1998). In diabetic patients, the saturated fatty acid amount was higher than in control and at the same time polyunsaturated fatty acid levels were lower than control (Prisco et al., 1989). Moreover, it has been evidenced a decrease in cholesterol/phospholipids ratio (Maksina et al., 1992; Mawatari et al., 2004) with a concomitant increase in sphingomyelin/phosphatidylcholine ratio. This situation may cause, at least in part, RBC function abnormalities and insulin resistance, because of inconvenient membrane fluidity. Previous studies have reported in plasma of diabetic patients and rats, high levels of oxidized lipids-derived aldehydes (Sato et al., 1979; Matkovics et al., 1982; Kaji et al., 1985; Uzel et al., 1987; Dohi et al., 1988). Further in vitro studies have reported that, damaging effects of hydrogen peroxide on RBC of diabetic patients is more relevant with respect to control ones (Matkovics et al., 1982; Uzel et al., 1987). Oxidized lipids, such as TBARS and conjugated dienes localized in RBC membranes, favor vascular defects reported in diabetes patients (Baynes, 1991; Jain et al., 1989). It is not yet known the mechanism responsible for hyperglycemia-induced membrane lipid peroxidation. It has been also reported that lipid peroxidation levels are correlated with the levels of HbA1c (Jain et al., 1989), as well as the 7-oxocholesterol/cholesterol and conjugated linoleic acid/linoleic acid ratios (Inouye et al., 1998, 1999). Some articles report that glucose reduces oxygen, leading to formation of aldehydes, H2O2 and ROS, resulting in oxidative stress and MDA (Carrell et al., 1975; Ramasarma, 1982; Halliwell and Gutteridge, 1984).
AGE (Basta, 2008) found in high levels in diabetic RBC affect cell survival, affecting protein integrity involved in membrane structure (Elkrief et al., 2016). Previous evidences show that increased blood glucose levels cause RBC membrane protein glycation, resulting in higher cell fragility (Hatanaka et al., 2016). Higher glycosylation levels affect cytoskeleton, resulting (Cho et al., 2008) in morphologically abnormal RBC with decreased life span (Labrouche et al., 1996). Serum protein glycation causes modification in RBC proteins and modulates their biological or structural function (Cho et al., 2008). Among RBC membrane proteins, the glucose transporter-1 (Glut-1) is responsible for basal glucose uptake and transport across the plasma membrane (Kawano et al., 1999). Several evidences showed that Glut-1 is more susceptible for glycation and its increased structural alteration in diabetes causes cellular and tissue damage (Bonadonna et al., 1996).
Adhesion to Endothelium
Adhesion of diabetic RBC to endothelium is mediated by a specific interaction between AGE, present on the RBC and a specific receptor on the endothelium. Consistent with this hypothesis, diabetic RBC of rats were able to interact with blood vessels receptor for advanced glycation end products (RAGE), and this event was followed by oxidative stress generation (Wautier et al., 1994). Furthermore, consequence of the RBC/endothelium interaction results in several perturbations such as an increased vessel permeability and interleukin-6 (IL-6) production. The oxidant stress secondary to RBC adhesion induces the activation of NFκB. The presence of RAGE in different cell types suggests that it could be involved in the genesis of diabetic complications, although the exact involvement of the AGE–RAGE interaction needs additional evidence. Inhibition of nitric oxide (NO) formation by nitro-L-arginine, potentiates the adhesion of RBC from diabetic patients to endothelium (Grossin et al., 2009). By contrast, the addition of NO donors (NOR-3, SIN-1 or SNAP) reduced or inhibited adhesion of RBC from diabetic patients measured in flow conditions (Grossin et al., 2009).
Alterations in RBC Deformability
Alterations in membrane lipid asymmetry and composition, as well as cytoskeletal ones, alter RBC shape and deformability, subsequently responsible for reduced RBC membrane integrity, when encountering shear stresses (Bennett-Guerrero et al., 2007). Structural alterations in RBC are reflected to the functionality of the cell. Previous data, supported by SEM visual analysis, have reported that RBC from diabetic patients differ in shape and size from RBC of healthy subjects (Buys et al., 2013). In addition, AFM analysis showed that T2DM RBC showed several structural and morphological alterations (Buys et al., 2013). Previously it has been observed an alteration in T2DM RBC ultrastructure, probably due to iron overcharge, that caused the polymerization of fibrinogen (Lipinski and Pretorius, 2013).
Low hemoglobin (Hb) levels is an indication of anemia and has the effect of inhibiting RBC from transporting oxygen to different tissues.
Anemia is easily found in people with diabetes and contributes to the pathogenesis of complications related to diabetes (Astor et al., 2002), especially in cases of renal dysfunction (Dikow et al., 2001; Herzog et al., 2008). A positive correlation was found between anemia, retinopathy (Qiao et al., 1997) and somatic neuropathy in T2DM patients (Mezzano et al., 2003; Thomas et al., 2004; Herzog et al., 2008).
Chung et al. (2017) have demonstrated a correlation with cardiovascular autonomic neuropathy, supporting the hypothesis that anemia triggers neuronal injury (Mezzano et al., 2003; Thomas et al., 2004; Herzog et al., 2008).
The responsible mechanism is still not well understood, but bilirubin originated mainly by heme degradation (Berk et al., 1969), could play a central role due to its antioxidant mediated effects (Stocker et al., 1987; Kapitulnik, 2004).
Moreover, hyperglycemia is linked with an over-expression of proinflammatory cytokines (IL-6, TNF-α and NFkB; Martínez-Pérez et al., 2013; Angelousi and Larger, 2015) that lead to diabetic cardiovascolar complication and anemia (Barbieri et al., 2015). In particular IL-6 has an antierythropoietic effect promoting immature RBC apoptosis, ultimately responsible for Hb reduction (Fava et al., 2001; Angelousi and Larger, 2015).
Altered RBC Functions in Alzheimer’s Disease
In last years, Aβ was found in peripheral plasma blood (Scheuner et al., 1996; Mehta et al., 2000; van Oijen et al., 2006; Graff-Radford et al., 2007) where it interacts with RBC, leading to impairment of its function (Mattson et al., 1997; Clementi et al., 2007; Mohanty et al., 2008), suggesting that this event could promote AD.
In particular, in AD RBC, have also been described physical alterations in membrane proteins (Kay et al., 1994), in the Ca++ permeability (Engström et al., 1995), in the antioxidant enzyme activities and morphological perturbations (Delibas et al., 2002) including Aβ-induced RBC suicidal death (i.e., eryptosis; Lang and Lang, 2015). There have been reports of links between RBC and AD. Some of these are highlighted below.
There is increasing attention to the vascular dysfunction as a possible cause of AD (de la Torre, 2002). In AD RBC, it has been reported a decrease in surface area, an increase in cell volume and alteration in membrane composition, leading to deformability decrease (Rifkind et al., 2002). Our recent in vitro data show a correlation between membrane alteration, signaling pathways activation and reduced RBC function (Carelli-Alinovi et al., 2016a). In AD patients, altered values for blood viscosity, mean corpuscular cell volume and RBC aggregation have been reported (Chang et al., 2007). An additional factor that can influence the oxygen delivery function in AD patients is the ability of RBC to adhere to the vasculature, by a mechanism mediated by Aβ. This kind of interaction causes a decrease in cell survival and the generation of oxidative stress and inflammatory condition (Nakagawa et al., 2011). Thus, authors suggested that Aβ and RBC interaction is responsible for blood flow alteration particularly at the cerebral level with amyloidosis.
Factors other than 2,3-DPG may affect the hemoglobin affinity to oxygen (Samaja et al., 2003). However, the relationship is established between the RBC concentration of 2,3-DPG and tissue hypoxia under various conditions. Thus, all above observations support the hypothesis that the chronic enhancement in the rate of active transport in RBC from AD patients leading to the decrease in the concentrations of ATP (Kosenko et al., 2012) and 2,3-DPG (Kaminsky et al., 2013), can result in increased hemoglobin affinity for oxygen, leading to impaired oxygen delivery to tissues (Aliev et al., 2009), which results in cognitive decline. In patients with AD, characteristic reduction of cerebral perfusion and metabolism occurs (de la Torre, 2002; Aliev et al., 2011) which inhibit the optimal delivery of glucose and oxygen (de la Torre and Aliev, 2005). The dysregulation of neuronal glucose metabolism in AD may result in a decrease in enzymatic activities of hexokinase (EC 184.108.40.206; Marcus and Freedman, 1997), phosphofructokinase (EC 220.127.116.11; Meier-Ruge et al., 1984), pyruvate dehydrogenase (EC 18.104.22.168) and enzymes of the tricarboxylic acid cycle (Bubber et al., 2005), and various other effects including the desensitization of the neuronal IR (Hoyer, 2000), impaired glucose transporter at the blood-brain barrier (BBB; Kalaria and Harik, 1989). At this regard, recently Kosenko et al. (2014) measured some parameters of adenine nucleotide metabolism, glycolysis, pentose phosphate pathway and the 2,3-DPG shunt in RBC from AD and age matched and young controls. From these results, it is clear that intracellular ATP levels, total adenine nucleotide pool size, and the ATP/ADP ratio were similar in RBC from AD patients and age-matched controls and lower than in young controls (Kosenko et al., 2012). However, activities of most of the enzymes such as hexokinase, glucose-6-phosphate isomerase (EC 22.214.171.124), phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase (EC 126.96.36.199), phosphoglycerate kinase (EC 188.8.131.52), pyruvate kinase (EC 184.108.40.206), lactate dehydrogenase (EC 220.127.116.11), glucose-6-phosphate dehydrogenase (EC 18.104.22.168), 6-phosphogluconate dehydrogenase (EC 22.214.171.124) and Na/K-ATPase, as well as the cytosolic NAD/NADH ratio, pyruvate and lactate levels, were higher in AD compared to controls, indicating an increase in RBC glycolysis and ion fluxes (Kaminsky et al., 2012, 2013).
It has been shown that in late onset patients, RBC membrane glucose transporter protein 1 (GLUT1) and IR, as well as ATP-binding cassette transporter sub-family A member 1 (ABCA1) and ATP-binding cassette sub-family G member 2 (ABCG2), have higher levels of expression (Várady et al., 2015). For what concerns the early onset AD, it has been reported the same behavior outlined in the late-onset form for GLUT1 and IR, on the other hand no changes have been observed for RBC ABCA1, ABCG2, plasma-membrane Ca(2+)-ATPase (PMCA) and ATP binding cassette subfamily B member 6 (ABCB6; Várady et al., 2015). Generally, GLUT1 expression is modulated by glucose, hypoxia, insulin and growth hormones (Guo et al., 2005; Chen et al., 2015), and it has been shown that RBC GLUT1 expression is modulated by plasma elevated glucose levels (Harik et al., 1991). In the cases examined, where an up-regulation of GLUT1 and INSR was observed, a systemic hyper-glycemia was not present. Based on the relevant literature (Querfurth and LaFerla, 2010; Huang and Mucke, 2012), it could be hypothesized that GLUT1 and INSR increased levels, originate from transporter upregulation in endothelial cells of blood brain barrier due to brain hypoxia. IR level increase, could be caused by the insulin resistance in CNS (Querfurth and LaFerla, 2010; Huang and Mucke, 2012). Protein Kinase C (PKC) undergoes alteration in brain (Pascale et al., 2007) and in peripheral tissues in AD (Govoni et al., 1993; Solerte et al., 1998). It plays a relevant role in AD physiopathology in brain, because it is involved in the transduction pathway and changes that occurs include, expression level and translocation (Pascale et al., 2007). The PKC role in RBC is similar to brain isoform. Band 3, a transmembrane protein in RBC, has the same role in brain and it becomes phosphorylated by PKC and it has the same alterations observed in AD brain and RBC. These modifications include an altered conformation recognized by antibodies, a decrease in anion transport and in 32P-phosphate labeling (Bosman et al., 1991; Kay and Goodman, 1997). It could be suggested that band 3 alterations could be linked to an altered PKC activity. Our previous studies have shown that activation of RBC PKC after Aβ exposition could play a key role in oxidative imbalance, occurring following Aβ exposure (Carelli-Alinovi et al., 2015a). RBC mechanical properties are regulated by RBC PKC isoforms, caspase 3 and NO produced within the cell (Misiti et al., 2008; Carelli-Alinovi et al., 2015b).
In RBC with high ROS level it is easy to find higher levels of oxidized hemoglobin (metHb) that is unable to carry oxygen. Following incubation of RBC with different aggregate forms of Aβ peptides and Cu2+ i.e., mainly protofibril, it has been found that Cu2+-increased RBC oxidative stress. Oxidative stress leads to Hb oxidation, to the onset of heme degradation products on RBC membrane and to reduced ability to deform its shape.
Recent experiments have shown that band 3 is degraded by caspase 3 in Aβ treated RBC (Clementi et al., 2007), leading to band 3/glycolytic enzymes interactions abrogation (Mandal et al., 2003). This leads to an alteration of RBC metabolism (Galtieri et al., 2002), implying that, AD RBC have an increased risk of oxidative damage. At this regard, caffeine, a largely known antioxidant, reduced Aβ-induced toxicity in RBC (Carelli-Alinovi et al., 2016b). Although still controversial, malondialdehyde (MDA) levels of RBC membrane increase in AD patients (Skoumalová and Hort, 2012). RBC abnormalities might indicate the progression of AD oxidative damage. AD RBC have a greater membrane instability when exposed to H2O2, compared with controls cells (Gilca et al., 2014). SOD activity protects cell but above a certain threshold, SOD is no longer able to protect and, on the contrary exalts peroxidation (Michiels et al., 1994). Therefore, SOD contributes to cell damage, favoring nitro-tyrosine formation in proteins. Previous articles suggested SOD as a peripheral marker of AD, reporting an increase in SOD activity in AD patient’s RBC (Serra et al., 1994, 2001).
Many studies have been conducted in an attempt to demonstrate a correlation between anemia and the development of the AD, but the results have often been discordant (Beard et al., 1997; Atti et al., 2006).
Low Hb levels could be a marker for ischemia, hypoxia-associated changes in hypoxia inducible factor (HIF) and erythropoietin levels, as well as alteration in heme regulation. Shah et al. (2011) demonstrated that hemoglobin levels were linked with cognitive decline. Chronic kidney disease associated with low Hb levels, could cause cerebral hypoxia, through a mechanism involving HIF and erythropoietin (Nangaku et al., 2008). At this regard, it has been suggested that a reduction in brain erythropoietin receptors (Maiese et al., 2005; Hasselblatt et al., 2006; Assaraf et al., 2007) increase neuronal degeneration.
Moreover, low hemoglobin levels expose RBC to a greater fragility, leading to an overload of heme molecules to be processed by astroglia brain. Elevated circulating free heme is able to over stimulate the hemo-oxigenase-1 activity, responsible for an increased oxidative stress, observed especially in sub-clinical AD subjects (Hascalovici et al., 2009).
RBC containing HbF are less vulnerable to oxidant injury with respect to those containing HbA, than they produce less Hb and heme, both of the have toxic effects upon the vascular cells. Consequently, elevated HbF could decrease hypo-perfusion and inflammation at brain level, and might be a protective factor for AD (Fallahzadeh et al., 2009). It has been also reported that lower hemoglobin levels are correlated with cognitive impairment and AD (Faux et al., 2014).
Long-Chain Omega-3 Polyunsaturated Fatty Acids (PUFA)
Low levels of docosahexaenoic acid (DHA) were measured in AD RBC membranes (Wang et al., 2008), in fact it has been found that, in rat models, PUFAs supplementation was able to ameliorate the cognitive deficit (Hashimoto et al., 2002, 2006, 2008). DHA can change membrane composition, because it acts on cholesterol, on fatty acid composition and enhances antioxidant defenses.
Anti Diabetic Therapy and Alzheimer’s Disease
Recent reports show that some antidiabetic drugs are able to induce neuronal survival, leading to clinical improvement of memory and cognition in different clinical settings. Studies on the effects of insulin therapy on the cognitive functions of dementia patients are controversial, some of these suggest that insulin increases the risk of dementia in diabetes patients, on the other hand further studies indicate that insulin slow down the cognitive decline in AD patients (Morris and Burns, 2012). Other drugs in addition to insulin such as metformin (Gupta et al., 2011), peroxisome proliferator–activated receptor (PPARγ; Jahrling et al., 2014), and incretins (Drucker, 2001) investigated for T2DM might potentially be beneficial for Alzheimer’s patients as well.
Anti-RBC Therapy and Alzheimer’s Disease
As previously reported, RBC play a key role in T2DM and AD-associated vascular complications by increasing oxidative stress and may therefore favor an increased risk of developing AD in T2DM patients. However, several studies showed effectiveness of some antioxidants, no data are yet available as to whether antioxidants protect against AD. Reasons for these results might include, in part, BBB permeability, inappropriate timing of administration, or suboptimal drug levels at the target site in the CNS (Rutten et al., 2002; Gilgun-Sherki et al., 2003).
Conclusions and Future Directions
Taking into account the literature discussed in this review, a strong correlation came out between T2DM and AD. In particular, it has been reported that T2DM subjects are at an increased risk of developing AD. Although both disorders possess several overlapping features, RBC abnormalities are relevant events and, at the same time, it is a “good indicator” of what happens at vascular level. Examples of this innovative idea, derive from recent literature focused on the understanding of RBC abnormalities that involve the impairment of RBC morphology, deformability, and function leading to vascular dysfunctions. Furthermore, and because RBC are major blood sources of ROS, the impairment of RBC functionality is accompanied by oxidative stress-related events. On this basis, altered RBCs following oxidative stress could be considered as a probable marker linkage for AD and T2DM. It is reasonable to enunciate that the current knowledge on the involvement of altered RBC dynamics in the pathogenesis of both AD and T2DM are still at an elementary stage, but it probable that elevated oxidative stress in RBC at vascular level both in AD and T2DM patients could combine with other factors, responsible for an increased risk of developing AD in T2DM patients. Furthermore, high levels of arachidonic acid and low levels of docosapentaenoic acid levels in RBC were observed in subjects with high neocortical beta-amyloid load, a feature of preclinical AD (Goozee et al., 2017), suggesting that inflammation and oxidative stress are early features of preclinical AD.
In light of its significant advancement from both clinical research and therapeutic application perspectives, we look ahead major research efforts being drawn to this field and more approaches being formulated soon. We also presume that finally these findings will be translated into novel drugs and effective therapies against both AD and T2DM triggered by RBC dysfunctions. The understanding of the molecular basis of these pathologies in RBC has the advantage to design a non-invasive diagnostic method, compared to the currently available techniques. Furthermore, it has been suggested that some of the drug currently used for T2DM might potentially be beneficial for Alzheimer’s patients as well.
FM and CC-A: substantial contributions to the conception or design of the work; drafting the work or revising it critically for important intellectual content agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; FM: final approval of the version to be published.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Thisresearch was supported by grants of the University of Cassino and Lazio Meridionale (FAR 2016).
Aliev, G., Li, Y., Palacios, H. H., and Obrenovich, M. E. (2011). Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases. Recent Pat. Cardiovasc. Drug Discov. 6, 222–241. doi: 10.2174/157489011797376942
Aliev, G., Palacios, H. H., Walrafen, B., Lipsitt, A. E., Obrenovich, M. E., and Morales, L. (2009). Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease. Int. J. Biochem. Cell Biol. 41, 1989–2004. doi: 10.1016/j.biocel.2009.03.015
Assaraf, M. I., Diaz, Z., Liberman, A., Miller, W. H. Jr., Arvanitakis, Z., Li, Y., et al. (2007). Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment. J. Neuropathol. Exp. Neurol. 66, 389–398. doi: 10.1097/nen.0b013e3180517b28
Astor, B. C., Muntner, P., Levin, A., Eustace, J. A., and Coresh, J. (2002). Association of kidney function with anemia: the third national health and nutrition examination survey (1988–1994). Arch. Intern. Med. 162, 1401–1408. doi: 10.1001/archinte.162.12.1401
Atti, A. R., Palmer, K., Volpato, S., Zuliani, G., Winblad, B., and Fratiglioni, L. (2006). Anemia increases the risk of dementia in cognitively intact elderly. Neurobiol. Aging 27, 278–284. doi: 10.1016/j.neurobiolaging.2005.02.007
Banks, W. A., Jaspan, J. B., and Kastin, A. J. (1997). Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin. Peptides 18, 1577–1584. doi: 10.1016/s0196-9781(97)00238-6
Barbieri, J., Fontela, P. C., Winkelmann, E. R., Zimmermann, C. E., Sandri, Y. P., Mallet, E. K., et al. (2015). Anemia in Patients with type 2 diabetes mellitus. Anemia 2015:354737. doi: 10.1155/2015/354737
Baskin, D. G., Stein, L. J., Ikeda, H., Woods, S. C., Figlewicz, D. P., Porte, D., et al. (1985). Genetically obese Zucker rats have abnormally low brain insulin content. Life Sci. 36, 627–633. doi: 10.1016/0024-3205(85)90166-3
Basta, G. (2008). Receptor for advanced glycation end products and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis 196, 9–21. doi: 10.1016/j.atherosclerosis.2007.07.025
Beard, C. M., Kokmen, E., O’Brien, P. C., Anía, B. J., and Melton, L. J. III (1997). Risk of Alzheimer’s disease among elderly patients with anemia: population-based investigations in Olmsted County Minnesota. Ann. Epidemiol. 7, 219–224. doi: 10.1016/S1047-2797(97)00015-X
Beisswenger, P. J., Drummond, K. S., Nelson, R. G., Howell, S. K., Szwergold, B. S., and Mauer, M. (2005). Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress. Diabetes 54, 3274–3281. doi: 10.2337/diabetes.54.11.3274
Bennett-Guerrero, E., Veldman, T. H., Doctor, A., Telen, M. J., Ortel, T. L., Reid, T. S., et al. (2007). Evolution of adverse changes in stored RBCs. Proc. Natl. Acad. Sci. U S A 104, 17063–17068. doi: 10.1073/pnas.0708160104
Beydoun, M. A., Lhotsky, A., Wang, Y., Dal Forno, G., An, Y., Metter, E. J., et al. (2008). Association of adiposity status and changes in early to mid-adulthood with incidence of Alzheimer’s disease. Am. J. Epidemiol. 168, 1179–1189. doi: 10.1093/aje/kwn229
Biessels, G. J., and Kappelle, L. J. (2005). Increased risk of Alzheimer’s disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology? Biochem. Soc. Trans. 33, 1041–1044. doi: 10.1042/bst20051041
Boas, F. E., Forman, L., and Beutler, E. (1998). Phosphatidylserine exposure and red cell viability in red cell aging and in haemolytic anemia. Proc. Natl. Acad. Sci. U S A 95, 3077–3081. doi: 10.1073/pnas.95.6.3077
Bonadonna, R. C., Del Prato, S., Bonora, E., Saccomani, M. P., Gulli, G., Natali, A., et al. (1996). Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM. Diabetes 45, 915–925. doi: 10.2337/diabetes.45.7.915
Bosman, G. J., Bartholomens, I. G., De Man, A. J., Van Kalmthout, P. J. C., and De Grip, W. J. (1991). Erythrocyte membrane characteristics indicate abnormal cellular aging in patients with Alzheimer’s disease. Neurobiol. Aging 12, 13–18. doi: 10.1016/0197-4580(91)90033-g
Bubber, P., Haroutunian, V., Fisch, G., Blass, J. P., and Gibson, G. E. (2005). Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann. Neurol. 57, 695–703. doi: 10.1002/ana.20474
Buys, A. V., Van Rooy, M.-J., Soma, P., Van Papendorp, D., Lipinski, B., and Pretorius, E. (2013). Changes in red blood cell membrane structure in type 2 diabetes: a scanning electron and atomic force microscopy study. Cardiovasc. Diabetol. 12:25. doi: 10.1186/1475-2840-12-25
Cao, D., Lu, H., Lewis, T. L., and Li, L. (2007). Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J. Biol. Chem. 282, 36275–36282. doi: 10.1074/jbc.M703561200
Carelli-Alinovi, C., Ficarra, S., Russo, A. M., Giunta, E., Barreca, D., Galtieri, A., et al. (2016b). Involvement of acetylcholinesterase and protein kinase C in the protective effect of caffeine against β-amyloid-induced alterations in red blood cells. Biochimie 121, 52–59. doi: 10.1016/j.biochi.2015.11.022
Carelli-Alinovi, C., Giardina, B., and Misiti, F. (2015a). Amyloid β peptide (1–42)-mediated antioxidant imbalance is associated with activation of protein kinase C in red blood cells. Cell Biochem. Funct. 33, 196–201. doi: 10.1002/cbf.3103
Carelli-Alinovi, C., Pirolli, D., Giardina, B., and Misiti, F. (2015b). Protein kinase C mediates caspase 3 activation: a role for erythrocyte morphology changes. Clin. Hemorheol. Microcirc. 59, 345–354. doi: 10.3233/ch-141845
Carro, E., and Torres-Aleman, I. (2004). The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer’s disease. Eur. J. Pharmacol. 490, 127–133. doi: 10.1016/j.ejphar.2004.02.050
Carro, E., Trejo, J. L., Spuch, C., Bohl, D., Heard, J. M., and Torres-Aleman, I. (2006). Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer’s-like neuropathology in rodents: new cues into the human disease? Neurobiol. Aging 27, 1618–1631. doi: 10.1016/j.neurobiolaging.2005.09.039
Chen, M., Inestrosa, G. S., Ross, H. L., and Fernandez, H. L. (1995). Platelets are the primary source of amyloid β-peptide in human blood. Biochem. Biophys. Res. Commun. 213, 96–103. doi: 10.1006/bbrc.1995.2103
Chi, N.-F., Chien, L.-N., Ku, H.-L., Hu, C.-J., and Chiou, H.-Y. (2013). Alzheimer disease and risk of stroke: a population-based cohort study. Neurology 80, 705–711. doi: 10.1212/wnl.0b013e31828250af
Chung, J. O., Park, S.-Y., Cho, D. H., Chung, D. J., and Chung, M. Y. (2017). Anemia, bilirubin, and cardiovascular autonomic neuropathy in patients with type 2 diabetes. Medicine 96:e6586. doi: 10.1097/MD.0000000000006586
Clementi, M. E., Giardina, B., Colucci, D., Galtieri, A., and Misiti, F. (2007). Amyloid-β peptide affects the oxygen dependence of RBC metabolism: a role for caspase 3. Int. J. Biochem. Cell Biol. 39, 727–735. doi: 10.1016/j.biocel.2006.11.013
Clementi, M. E., Pezzotti, M., Giardina, B., and Misiti, F. (2004). Methionine 35 oxidation reduces toxic effects of the amyloid β-protein fragment (31–35) on human red blood cell. Int. J. Biochem. Cell Biol. 10, 2066–2076. doi: 10.1016/j.biocel.2004.03.006
Clifton, P. M., and Nestel, P. J. (1998). Relationship between plasma insulin and erythrocyte fatty acid composition. Prostaglandins Leukot. Essent. Fatty Acids 59, 191–194. doi: 10.1016/s0952-3278(98)90062-x
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923. doi: 10.1126/science.8346443
de la Torre, J. C., and Aliev, G. (2005). Inhibition of vascular nitric oxide after rat chronic brain hypoperfusion: spatial memory and immunocytochemical changes. J. Cereb. Blood Flow Metab. 25, 663–672. doi: 10.1038/sj.jcbfm.9600057
Delibas, N., Ozcankaya, R., and Altuntas, I. (2002). Clinical importance of erythrocyte malondialdehyde levels as a marker for cognitive deterioration in patients with dementia of Alzheimer type A repeated study in 5-year interval. Clin. Biochem. 35, 137–141. doi: 10.1016/s0009-9120(02)00287-4
Ditzel, J., Jaeger, P., and Standl, E. (1978). An adverse effect of insulin on the oxygen-release capacity of red blood cells in nonacidotic diabetics. Metabolism 27, 927–934. doi: 10.1016/0026-0495(78)90136-1
Dohi, T., Kawamura, K., Morita, K., Okamoto, H., and Tsujimoto, A. (1988). Alteration of the plasma selenium concentrations and the activities of tissue peroxide metabolism enzymes in streptozotocin-induced diabetic rats. Horm. Metab. Res. 20, 671–675. doi: 10.1055/s-2007-1010914
Elkrief, L., Rautou, P. E., Sarin, S., Valla, D., Paradis, V., and Moreau, R. (2016). Diabetes mellitus in patients with cirrhosis: clinical implications and management. Liver Int. 36, 936–948. doi: 10.1111/liv.13115
Engström, I., Ronquist, G., Pettersson, L., and Waldenström, A. (1995). Alzheimer amyloid β-peptides exhibit ionophore-like properties in human erythrocytes. Eur. J. Clin. Invest. 25, 471–476. doi: 10.1111/j.1365-2362.1995.tb01732.x
Fallahzadeh, M. K., Borhani Haghighi, A., Namazi, M. R., and Fallahzadeh, M. H. (2009). β-thalassemia trait as a protective factor against Alzheimer disease. Alzheimer Dis. Assoc. Disord. 23, 186–187. doi: 10.1097/wad.0b013e31819cb582
Fava, S., Azzopardi, J., Ellard, S., and Hattersley, A. T. (2001). ACE gene polymorphism as a prognostic indicator in patients with type 2 diabetes and established renal disease. Diabetes Care 24, 2115–2120. doi: 10.2337/diacare.24.12.2115
Galtieri, A., Tellone, E., Romano, L., Misiti, F., Bellocco, E., Ficarra, S., et al. (2002). Band-3 protein function in human erythrocytes: effect of oxygenation-deoxygenation. Biochim. Biophys. Acta 1564, 214–218. doi: 10.1016/s0005-2736(02)00454-6
Gilca, M., Lixandru, D., Gaman, L., Vîrgolici, B., Atanasiu, V., and Stoian, I. (2014). Erythrocyte membrane stability to hydrogen peroxide is decreased in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 28, 358–363. doi: 10.1097/WAD.0000000000000026
Goozee, K., Chatterjee, P., James, I., Shen, K., Sohrabi, H. R., Asih, P. R., et al. (2017). Alterations in erythrocyte fatty acid composition in preclinical Alzheimer’s disease. Sci. Rep. 7:676. doi: 10.1038/s41598-017-00751-2
Govoni, S., Bergamaschi, S., Racchi, M., Battaini, F., Binetti, G., Bianchetti, A., et al. (1993). Cytosolic protein kinase C downregulation in fibroblasts from Alzheimer’s disease patients. Neurology 43, 2581–2586. doi: 10.1212/wnl.43.12.2581
Graff-Radford, N. R., Crook, J. E., Lucas, J., Boeve, B. F., Knopman, D. S., Ivnik, R. J., et al. (2007). Association of low plasma Aβ42/Aβ40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch. Neurol. 64, 354–362. doi: 10.1001/archneur.64.3.354
Grossin, N., Wautier, M. P., and Wautier, J. L. (2009). Red blood cell adhesion in diabetes mellitus is mediated by advanced glycation end product receptor and is modulated by nitric oxide. Biorheology 46, 63–72. doi: 10.3233/BIR-2009-0519
Guo, X., Geng, M., and Du, G. (2005). Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier. Biochem. Genet. 43, 175–187. doi: 10.1007/s10528-005-1510-5
Gupta, A., Bisht, B., and Dey, C. S. (2011). Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology 60, 910–920. doi: 10.1016/j.neuropharm.2011.01.033
Harik, S. I., Behmand, R. A., and Arafah, B. M. (1991). Chronic hyperglycemia increases the density of glucose transporters in human erythrocyte membranes. J. Clin. Endocrinol. Metab. 72, 814–818. doi: 10.1210/jcem-72-4-814
Hascalovici, J. R., Vaya, J., Khatib, S., Holcroft, C. A., Zukor, H., Song, W., et al. (2009). Brain sterol dysregulation in sporadic AD and MCI: relationship to heme oxygenase-1. J. Neurochem. 110, 1241–1253. doi: 10.1111/j.1471-4159.2009.06213.x
Hashimoto, M., Hossain, S., Shimada, T., and Shido, O. (2006). Docosahexaenoic acid-induced protective effect against impaired learning in amyloid β-infused rats is associated with increased synaptosomal membrane fluidity. Clin. Exp. Pharmacol. Physiol. 33, 934–939. doi: 10.1111/j.1440-1681.2006.04467.x
Hashimoto, M., Hossain, S., Shimada, T., Sugioka, K., Yamasaki, H., Fujii, Y., et al. (2002). Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer’s disease model rats. J. Neurochem. 81, 1084–1091. doi: 10.1046/j.1471-4159.2002.00905.x
Hashimoto, M., Shahdat, H., Yamashita, S., Katakura, M., Tanabe, Y., Fujiwara, H., et al. (2008). Docosahexaenoic acid disrupts in vitro amyloid β(1–40) fibrillation and concomitantly inhibits amyloid levels in cerebral cortex of Alzheimer’s disease model rats. J. Neurochem. 107, 1634–1646. doi: 10.1111/j.1471-4159.2008.05731.x
Hasselblatt, M., Ehrenreich, H., and Sirén, A. L. (2006). The brain erythropoietin system and its potential for therapeutic exploitation in brain disease. J. Neurosurg. Anesthesiol. 18, 132–138. doi: 10.1097/00008506-200604000-00007
Hatanaka, H., Hanyu, H., Fukasawa, R., Sato, T., Shimizu, S., and Sakurai, H. (2016). Peripheral oxidative stress markers in diabetes-related dementia. Geriatr. Gerontol. Int. 16, 1312–1318. doi: 10.1111/ggi.12645
Helzner, E. P., Luchsinger, J. A., Scarmeas, N., Cosentino, S., Brickman, A. M., Glymour, M. M., et al. (2009). Contribution of vascular risk factors to the progression in Alzheimer disease. Arch. Neurol. 66, 343–348. doi: 10.1001/archneur.66.3.343
Ho, L., Qin, W., Pompl, P. N., Xiang, Z., Wang, J., Zhao, Z., et al. (2004). Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J. 18, 902–904. doi: 10.1096/fj.03-0978fje
Huang, C.-C., Chung, C.-M., Leu, H.-B., Lin, L.-Y., Chiu, C.-C., Hsu, C.-Y., et al. (2014). Diabetes mellitus and the risk of Alzheimer’s disease: a nationwide population based study. PLoS One 9:e87095. doi: 10.1371/journal.pone.0087095
Inouye, M., Hashimoto, H., Mio, T., and Sumino, K. (1998). Levels of lipid peroxidation product and glycated hemoglobin A1c in the erythrocytes of diabetic patients. Clin. Chim. Acta 276, 163–172. doi: 10.1016/s0009-8981(98)00112-0
Jahrling, J. B., Hernandez, C. M., Denner, L., and Dineley, K. T. (2014). PPARγ recruitment to active ERK during memory consolidation is required for Alzheimer’s disease-related cognitive enhancement. J. Neurosci. 34, 4054–4063. doi: 10.1523/JNEUROSCI.4024-13.2014
Jain, S. K., Mohandas, N., Clark, M., and Shohet, S. B. (1983). The effect of malonyldialdehyde, a product of lipid peroxidation, on the deformability, dehydration and 51-Cr-survival of erythrocytes. Br. J. Haematol. 53, 247–255. doi: 10.1111/j.1365-2141.1983.tb02018.x
Jayakumar, R., Kusiak, J. W., Chrest, F. J., Demehin, A. A., Murali, J., Wersto, R. P., et al. (2003). Red cell perturbations by amyloid β-protein. Biochim. Biophys. Acta 1622, 20–28. doi: 10.1016/S0304-4165(03)00101-6
Kaiyala, K. J., Prigeon, R. L., Kahn, S. E., Woods, S. C., and Schwartz, M. W. (2000). Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49, 1525–1533. doi: 10.2337/diabetes.49.9.1525
Kaji, H., Kurasake, M., Ito, K., Saito, T., Saito, K., Niioka, T., et al. (1985). Increased lipoperoxide value and glutathione peroxidase activity in blood plasma of type 2 (non-insulin dependent) diabetic women. Klin. Wochenschr. 63, 765–768. doi: 10.1007/bf01733829
Kalaria, R. N., and Harik, S. I. (1989). Reduced glucose transporter at the blood brain barrier and in cerebral cortex in Alzheimer disease. J. Neurochem. 53, 1083–1088. doi: 10.1111/j.1471-4159.1989.tb07399.x
Kaminsky, Y., Poghosyan, A., Tikhonova, L., Palacios, H. H., Kamal, M. A., Kosenko, E., et al. (2012). Glycolytic and proteolytic metabolism in erythrocytes from elderly and demented patients. Am. J. Neuroprotect. Neuroregener. 4, 73–77. doi: 10.1166/ajnn.2012.1039
Kaminsky, G. Y., Reddy, V. P., Ashraf, G. M., Ahmad, A., Benberin, V. V., Kosenko, E. A., et al. (2013). Age-related defects in erythrocyte 2,3-Diphosphoglycerate metabolism in dementia. Aging Dis. 4, 244–255. doi: 10.14336/AD.2013.0400244
Kawano, Y., Rincon, J., Soler, A., Ryder, J. W., Nolte, L. A., Zierath, J. R., et al. (1999). Changes in glucose transport and protein kinase-C β2 in rat skeletal muscle induced by hyperglycemia. Diabetologia 42, 1071–1079. doi: 10.1007/s001250051273
Kay, M. M., and Goodman, J. (1997). Brain and erythrocyte anion transporter protein, band 3, as a marker for Alzheimer’s disease: structural changes detected by electron microscopy, phosphorylation and antibodies. Gerontology 43, 44–66. doi: 10.1159/000213835
Kosenko, E. A., Aliev, G., Tikhonova, L. A., Li, Y., Poghosyan, A. C., and Kaminsky, Y. G. (2012). Antioxidant status and energy state of erythrocytes in Alzheimer dementia: probing for markers. CNS Neurol. Disord. Drug Targets 11, 926–932. doi: 10.2174/1871527311201070926
Kosenko, E. A., Solomadin, I. N., Tikhonova, L. A., Reddy, V. P., Aliev, G., and Kaminsky, Y. G. (2014). Pathogenesis of Alzheimer disease: role of oxidative stress, amyloid-β peptides, systemic ammonia and erythrocyte energy metabolism. CNS Neurol. Disord. Drug Targets 13, 112–119. doi: 10.2174/18715273113126660130
Labrouche, S., Freyburger, G., Gin, H., Boisseau, M. R., and Cassagne, C. (1996). Changes in phospholipid composition of blood cell membranes (erythrocyte, platelet, and polymorphonuclear) in different types of diabetes-clinical and biological correlations. Metab. Clin. Exp. 45, 57–71. doi: 10.1016/s0026-0495(96)90200-0
Li, X., Lu, F., Tian, Q., Yang, Y., Wang, Q., and Wang, J. Z. (2006). Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture. J. Neural Transm. (Vienna) 113, 93–102. doi: 10.1007/s00702-005-0303-7
Lipinski, B., and Pretorius, E. (2013). The role of iron-induced fibrin in the pathogenesis of Alzheimer’s disease and the protective role of magnesium. Front. Hum. Neurosci. 7:735. doi: 10.3389/fnhum.2013.00735
Mandal, D., Baudin-Creuza, V., Bhattacharyya, A., Pathak, S., Delaunay, J., Kundu, M., et al. (2003). Caspase 3-mediated proteolysis of the N-terminal cytoplasmic domain of the human erythroid anion exchanger 1 (band 3). J. Biol. Chem. 278, 52551–52558. doi: 10.1074/jbc.M306914200
Marcus, D. L., and Freedman, M. L. (1997). Decreased brain glucose metabolism in microvessels from patients with Alzheimer’s disease. Ann. N Y Acad. Sci. 826, 248–253. doi: 10.1111/j.1749-6632.1997.tb48476.x
Martínez-Pérez, B., de la Torre-Díez, I., and López-Coronado, M. (2013). Mobile health applications for the most prevalent conditions by the World Health Organization: review and analysis. J. Med. Internet Res. 15:e120. doi: 10.2196/jmir.2600
Mattson, M. P., Begley, J. G., Mark, R. J., and Furukawa, K. (1997). Aβ25–35 induces rapid lysis of red blood cells: contrast with Aβ1–42 and examination of underlying mechanisms. Brain Res. 771, 147–153. doi: 10.1016/s0006-8993(97)00824-x
Mawatari, S., Saito, K., Murakami, K., and Fujino, T. (2004). Absence of correlation between glycated hemoglobin and lipid composition of erythrocyte membrane in type 2 diabetic patients. Metabolism 53, 123–127. doi: 10.1016/j.metabol.2003.07.016
Mehta, P. D., Pirttilä, T., Mehta, S. P., Sersen, E. A., Aisen, P. S., and Wisniewski, H. M. (2000). Plasma and cerebrospinal fluid levels of amyloid β proteins 1–40 and 1-42 in Alzheimer disease. Arch. Neurol. 57, 100–105. doi: 10.1001/archneur.57.1.100
Mezzano, S., Droguett, A., Burgos, M. E., Ardiles, L. G., Flores, C. A., Aros, C. A., et al. (2003). Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy. Kidney Int. Suppl. 64, S64–S70. doi: 10.1046/j.1523-1755.64.s86.12.x
Michiels, C., Raes, M., Toussaint, O., and Remacle, J. (1994). Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress. Free Radic. Biol. Med. 17, 235–248. doi: 10.1016/0891-5849(94)90079-5
Misiti, F., Carelli-Alinovi, C., Sampaolese, B., and Giardina, B. (2012). β-amyloid decreases detectable endothelial nitric oxide synthase in human erythrocytes: a role for membrane acetylcholinesterase. Cell Biochem. Funct. 30, 474–479. doi: 10.1002/cbf.2822
Misiti, F., Orsini, F., Clementi, M. E., Masala, D., Tellone, E., Galtieri, A., et al. (2008). Amyloid peptide inhibits ATP release from human erythrocytes. Biochem. Cell Biol. 86, 501–508. doi: 10.1139/O08-139
Mohanty, J. G., Eckley, D. M., Williamson, J. D., Launer, L. J., and Rifkind, J. M. (2008). Do red blood cell-β-amyloid interactions alter oxygen delivery in Alzheimer’s disease? Adv. Exp. Med. Biol. 614, 29–35. doi: 10.1007/978-0-387-74911-2_4
Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., and O’Neill, C. (2010). Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signaling. Neurobiol. Aging 31, 224–243. doi: 10.1016/j.neurobiolaging.2008.04.002
Morris, J. K., Vidoni, E. D., Honea, R. A., and Burns, J. M. (2014). Alzheimer’s disease neuroimaging initiative. Mpaired glycemia increases disease progression in mild cognitive impairment. Neurobiol. Aging 35, 585–589. doi: 10.1016/j.neurobiolaging.2013.09.033
Nakagawa, K., Kiko, T., Kuriwada, S., Miyazawa, T., Kimura, F., and Miyazawa, T. (2011). Amyloid β induces adhesion of erythrocytes to endothelial cells and affects endothelial viability and functionality. Biosci. Biotechnol. Biochem. 75, 2030–2033. doi: 10.1271/bbb.110318
Nelson, P. T., Smith, C. D., Abner, E. A., Schmitt, F. A., Scheff, S. W., Davis, G. J., et al. (2009). Human cerebral neuropathology of Type 2 diabetes mellitus. Biochim. Biophys. Acta 1792, 454–469. doi: 10.1016/j.bbadis.2008.08.005
Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). (2001). Pathological correlates of late-onset dementia in a multicentre, community-based population in England Wales. Lancet 357, 169–175. doi: 10.1016/s0140-6736(00)03589-3
Nicolay, J. P., Schneider, J., Niemoeller, O. M., Artunc, F., Portero-Otin, M., Haik, G. Jr., et al. (2006). Stimulation of suicidal erythrocyte death by methylglyoxal. Cell. Physiol. Biochem. 18, 223–232. doi: 10.1159/000097669
Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E. K., et al. (2001). Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767. doi: 10.1093/jnen/60.8.759
Ott, A., Stolk, R. P., van Harskamp, F., Pols, H. A., Hofman, A., and Breteler, M. M. (1999). Diabetes mellitus and the risk of dementia: the rotterdam study. Neurology 53, 1937–1942. doi: 10.1212/WNL.53.9.1937
Pascale, A., Amadio, M., Govoni, S., and Battaini, F. (2007). The aging brain, a key target for the future: the protein kinase C involvement. Pharmacol. Res. 55, 560–569. doi: 10.1016/j.phrs.2007.04.013
Peila, R., Rodriguez, B. L., and Launer, L. J. (2002). Type 2 diabetes, APOE gene and the risk for dementia, and related pathologies: the honolulu-asia aging study. Diabetes 51, 1256–1262. doi: 10.2337/diabetes.51.4.1256
Peila, R., Rodriguez, B. L., White, L. R., and Launer, L. J. (2004). Fasting insulin and incident dementia in an elderly population of Japanese-American men. Neurology 63, 228–233. doi: 10.1212/01.WNL.0000129989.28404.9b
Pescarmona, G. P., Bosia, A., and Ghigo, D. (1982). “Shortened red cell life span in diabetes: mechanism of hemolysis,” in Advances in Red Cell Biology, eds D. J. Weatherall, G. Fiorelli and S. Gorini (New York, NY: Raven), 391–397.
Peterson, C. M., Jones, R. L., Koenig, R. J., Melvin, E. T., and Lehrman, M. L. (1977). Reversible hematologic sequelae of diabetes mellitus. Ann. Intern. Med. 86, 425–429. doi: 10.7326/0003-4819-86-4-425
Petrovitch, H., White, L. R., Ross, G. W., Steinhorn, S. C., Li, C. Y., Masaki, K. H., et al. (2001). Accuracy of clinical criteria for AD in the honolulu-asia aging study, a population-based study. Neurology 57, 226–234. doi: 10.1212/WNL.57.2.226
Prisco, D., Paniccia, R., Coppo, M., Vanni, D., Rogasi, P. G., Tramontana, M., et al. (1989). Red blood cell lipid alterations in type II diabetes mellitus. Thromb. Res. 15, 751–758. doi: 10.1016/0049-3848(89)90139-4
Rutten, B. P., Steinbusch, H. W., Korr, H., and Schmitz, C. (2002). Antioxidants and Alzheimer’s disease: from bench to bedside (and back again). Curr. Opin. Clin. Nutr. Metab. Care 5, 645–651. doi: 10.1097/00075197-200211000-00006
Samaja, M., Crespi, T., Guazzi, M., and Vandegriff, K. D. (2003). Oxygen transport in blood at high altitude: role of the hemoglobin-oxygen affinity and impact of the phenomena related to hemoglobin allosterism and red cell function. Eur. J. Appl. Physiol. 90, 351–359. doi: 10.1007/s00421-003-0954-8
Sato, N., and Morishita, R. (2015). The roles of lipid and glucose metabolism in modulation of β-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease. Front. Aging Neurosci. 7:199. doi: 10.3389/fnagi.2015.00199
Satoh, M., Imazumi, K., Bessho, T., and Shiga, T. (1984). Increased erythrocyte aggregation in diabetes mellitus and its relationship to glycosylated hemoglobin and retinopathy. Diabetologia 27, 517–521. doi: 10.1007/bf00290387
Shah, R. C., Buchman, A. S., Wilson, R. S., Leurgans, S. E., and Bennett, D. A. (2011). Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis. Neurology 77, 219–226. doi: 10.1212/WNL.0b013e318225aaa9
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., et al. (1996). Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat. Med. 2, 864–870. doi: 10.1038/nm0896-864
Serra, J. A., Dominguez, R. O., de Lustig, E. S., Guareschi, E. M., Famulari, A. L., Bartolome, E. L., et al. (2001). Parkinson’s disease is associated with oxidative stress: comparison of peripheral antioxidant profiles in living Parkinson’s, Alzheimer’s and vascular dementia patients. J. Neural Transm. (Vienna) 108, 1135–1148. doi: 10.1007/s007020170003
Serra, J. A., Famulari, A. L., Kohan, S., Marschoff, E. R., Dominguez, R. O., and de Lustig, E. S. (1994). Copper-zinc superoxide dismutase activity in red blood cells in probable Alzheimer’s patients and their first-degree relatives. J. Neurol. Sci. 122, 179–188. doi: 10.1016/0022-510x(94)90297-6
Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., et al. (1992). Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 359, 325–327. doi: 10.1038/359325a0
Solerte, S. B., Fioravanti, M., Pascale, A., Ferrari, E., Govoni, S., and Battaini, F. (1998). Increased natural killer cell cytotoxicity in Alzheimer’s disease may involve protein kinase C dysregulation. Neurobiol. Aging 19, 191–199. doi: 10.1016/s0197-4580(98)00050-5
Stocker, R., Yamamoto, Y., McDonagh, A. F., Glazer, A. N., and Ames, B. N. (1987). Bilirubin is an antioxidant of possible physiological importance. Science 235, 1043–1046. doi: 10.1126/science.3029864
Takeda, S., Sato, N., Uchio-Yamada, K., Sawada, K., Kunieda, T., Takeuchi, D., et al. (2010). Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes. Proc. Natl. Acad. Sci. U S A 107, 7036–7041. doi: 10.1073/pnas.1000645107
Tolppanen, A. M., Lavikainen, P., Solomon, A., Kivipelto, M., Soininen, H., and Hartikainen, S. (2013). Incidence of stroke in people with Alzheimer disease: a national register-based approach. Neurology 80, 353–358. doi: 10.1212/WNL.0b013e31827f08c5
Townsend, M., Mehta, T., and Selkoe, D. J. (2007). Soluble Aβ inhibits specific signal transduction cascades common to the insulin receptor pathway. J. Biol. Chem. 282, 33305–33312. doi: 10.1074/jbc.M610390200
Uzel, N., Sivas, A., Uysal, M., and Oz, H. (1987). Erythrocyte lipid peroxidation and glutathione peroxidase activities in patients with diabetes mellitus. Horm. Metab. Res. 19, 89–90. doi: 10.1055/s-2007-1011748
van Oijen, M., Hofman, A., Soares, H. D., Koudstaal, P. J., and Breteler, M. M. (2006). Plasma Aβ1–40 and Aβ1–42 and the risk of dementia: a prospective case-cohort study. Lancet Neurol. 5, 655–660. doi: 10.1016/S1474-4422(06)70501-4
Várady, G., Szabó, E., Fehér, Á., Németh, A., Zámbó, B., Pákáski, M., et al. (2015). Alterations of membrane protein expression in red blood cells of Alzheimer’s disease patients. Alzheimers Dement. (Amst) 1, 334–338. doi: 10.1016/j.dadm.2015.06.007
Wali, R. K., Jaffe, S., Kumar, D., and Kalra, V. K. (1988). Alterations in organization of phospholipids in erythrocytes as factor in adherence to endothelial cells in diabetes mellitus. Diabetes 37, 104–111. doi: 10.2337/diabetes.37.1.104
Wang, W., Shinto, L., Connor, W. E., and Quinn, J. F. (2008). Nutritional biomarkers in Alzheimer’s disease: the association between carotenoids, n-3 fatty acids, and dementia severity. J. Alzheimers Dis. 13, 31–38. doi: 10.3233/jad-2008-13103
Wautier, J. L., Paton, R. C., Wautier, M. P., Pintigny, D., Abadie, E., Passa, P., et al. (1981). Increased adhesion of erythrocytes to endothelial cells in diabetes mellitus and its relation to vascular complications. N. Engl. J. Med. 305, 237–242. doi: 10.1056/nejm198107303050501
Wautier, J. L., Wautier, M. P., Schmidt, A. M., Anderson, G. M., Hori, O., Zoukourian, C., et al. (1994). Advanced glycation end products (AGEs) on the surface of diabetic erythrocytes bind to the vessel wall via a specific receptor inducing oxidant stress in the vasculature: a link between surface-associated AGEs and diabetic complications. Proc. Natl. Acad. Sci. U S A 91, 7742–7746. doi: 10.1073/pnas.91.16.7742
Keywords: Alzheimer’s disease, diabetes mellitus type 2, red blood cells, amyloid beta peptide, oxidative stress, vascular disease
Citation: Carelli-Alinovi C and Misiti F (2017) Erythrocytes as Potential Link between Diabetes and Alzheimer’s Disease. Front. Aging Neurosci. 9:276. doi: 10.3389/fnagi.2017.00276
Received: 24 March 2017; Accepted: 03 August 2017;
Published: 25 August 2017.
Edited by:Takeshi Ikeuchi, Niigata University, Japan
Reviewed by:Gjumrakch Aliev, GALLY International Biomedical Research, United States
Mitsuru Shinohara, Mayo Clinic Florida, United States
Copyright © 2017 Carelli-Alinovi and Misiti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Francesco Misiti, email@example.com