AMP-activated protein kinase: a potential player in Alzheimer’s disease

JOURNAL OF NEUROCHEMISTRY

| 2011 | 118 | 460–474

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doi: 10.1111/j.1471-4159.2011.07331.x

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*Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland  Department of Neurology, Kuopio University Hospital, Kuopio, Finland àDepartment of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland §Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland

Abstract AMP-activated protein kinase (AMPK) stimulates energy production via glucose and lipid metabolism, whereas it inhibits energy consuming functions, such as protein and cholesterol synthesis. Increased cytoplasmic AMP and Ca2+ levels are the major activators of neuronal AMPK signaling. Interestingly, Alzheimer’s disease (AD) is associated with several abnormalities in neuronal energy metabolism, for example, decline in glucose uptake, mitochondrial dysfunctions and defects in cholesterol metabolism, and in addition, with problems in maintaining Ca2+ homeostasis. Epidemiological studies have also revealed that many metabolic and cardiovascular diseases are risk factors for cognitive impairment and sporadic AD. Emerging studies indicate that AMPK signaling can regulate tau

protein phosphorylation and amyloidogenesis, the major hallmarks of AD. AMPK is also a potent activator of autophagic degradation which seems to be suppressed in AD. All these observations imply that AMPK is involved in the pathogenesis of AD. However, the responses of AMPK activation are dependent on stimulation and the extent of activating stress. Evidently, AMPK signaling can repress and delay the appearance of AD pathology but later on, with increasing neuronal stress, it can trigger detrimental effects that augment AD pathogenesis. We will outline the potential role of AMPK function in respect to various aspects affecting AD pathogenesis. Keywords: aging, Alzheimer’s disease, AMPK, autophagy, inflammation, tauopathy. J. Neurochem. (2011) 118, 460–474.

AMP-activated protein kinase (AMPK) is a Ser/Thr kinase which has a crucial role in the maintenance of energy metabolism at both cellular and whole-body levels (Lage et al. 2008; Steinberg and Kemp 2009; Canto and Auwerx 2010). Mammalian AMPK is a heterotrimeric complex assembled from catalytic a subunit (a1 and a2 isoforms) and regulatory b (b1 and b2) and c subunits (c1, c2, c3). The AMPK isoforms are commonly expressed, but they display clear tissue-specific expression patterns. In addition, the subunits can compose diverse complexes which can have different properties. The most characteristic feature of AMPK is its allosteric activation by increased concentration of AMP and thus it is a sensitive gauge for metabolic stress in cells (Steinberg and Kemp 2009). There are also three upstream kinases, which can activate AMPK by phosphorylating the a subunit at Thr172 in the regulatory T-loop

Received April 25, 2011; revised manuscript received/accepted May 26, 2011. Address correspondence and reprint requests to Antero Salminen, Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: antero.salminen@uef.fi Abbreviations used: AD, Alzheimer’s disease; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMPK, AMP-activated protein kinase; APP, amyloid-b peptide precursor protein; BACE1, b-amyloid converting enzyme 1; CAA, cerebral amyloid angiopathy; CaMKKb, Ca2+/calmodulin-dependent protein kinase kinase b; CREB, cAMPresponsive element-binding protein; CRTC-1, cAMP-regulated transcriptional co-activator-1; ER, endoplasmic reticulum; FOXO, forkhead box O; GLUT, glucose transporter; GSK3b, glycogen synthase kinase3b; HIF-1a, hypoxia-inducible factor-1a; IGF-1, insulin like growth factor-1; IL-6, interleukin-6; mTOR, mammalian target of rapamycin; NF-jB, nuclear factor-jB; PGC-1a, peroxisome proliferator-activated receptor-1a co-activator; PHF, paired helical filaments; PP, protein phosphatase; PS1, presenilin 1; SIRT1, silent information regulator 1.

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Fig. 1 Schematic illustration of the functional connections of AMPK signaling. Energy deficiency and a variety of other stresses can activate AMPK, either by increasing the AMP concentration or by triggering activation of three upstream protein kinases. Many hormones, for example, adiponectin and leptin, and several chemical compounds can switch on AMPK signaling. The AMPK signaling can be inhibited by AMPK phosphatases, such as PP2Ca and PP2A. AMPK has a number of downstream molecular targets which can directly or indirectly regulate different events in AD pathogenesis. The arrows indicate the activation of AMPK and the stopper shows inhibition of AMPK. Abbreviations: AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMPK, AMP-activated protein kinase; APP, amyloid-b peptide precursor protein; CaMKKb, Ca2+/calmodulin-dependent protein kinase kinase b; LKB1, Ser/Thr kinase STK11; PP, protein phosphatase; TAK1, transforming growth factor-b-activated protein kinase 1.

(Fig. 1). One of the upstream AMPK-activating kinases, Ca2+/calmodulin-dependent protein kinase kinase b (CaMKKb) is abundantly expressed in neurons (Nakamura et al. 2001) and activated by an increase in intracellular Ca2+ concentration and dysfunctions of Ca2+ balance can trigger AMPK signaling, in particular in neurons (Woods et al. 2005; Carling et al. 2008). Liver kinase B1, another upstream kinase of AMPK, is a tumor-suppressor kinase, which has several downstream targets via which it regulates energy metabolism, cell polarity and cell proliferation (Jansen et al. 2009). Liver kinase B1 controls, for example, the polarization of cortical neurons, but this is an AMPKindependent function (Barnes et al. 2007). The third AMPKactivating protein kinase is TAK1 (transforming growth factor-b-activated protein kinase 1) (Xie et al. 2006), but its role in AMPK activation and function in neurons needs to be clarified. Some hormones can also regulate the activity of AMPK, for example, adiponectin and leptin are potent activators of AMPK (Lim et al. 2010) (Fig. 1). Protein phosphatases PP2Ca and PP2A are crucial inhibitors of AMPK function (Sanders et al. 2007; Wu et al. 2007). Even though some of the factors controlling AMPK activity have already been identified, full understanding of the upstream regulation mechanisms of AMPK signaling still requires further studies. However, it seems that the control of AMPK

activation is context-dependent and tissue-specific (Mantovani and Roy 2011). The major role of AMPK is to stimulate energy production via glucose and lipid metabolism and to inhibit energy consuming functions, for example, synthesis of protein, fatty acids and cholesterol (Hardie 2008; Lage et al. 2008). AMPK signaling promotes glucose uptake and glycolysis potentiating energy production, for example, in heart and skeletal muscles. AMPK also increases fatty acid oxidation and through transcriptional regulation can increase mitochondrial biogenesis. Emerging studies also indicate that AMPK in hypothalamic neurons has a central role in the regulation of food intake (Lage et al. 2008). Feeding level and hormones regulate neuropeptide expression via AMPK activity in the hypothalamus and in that way they can adjust the whole-body energy homeostasis. In addition to energy metabolism, AMPK signaling can control many functions enhancing the adaptation to cellular and organismal stress, for example, by potentiating energy production through the activation of autophagocytosis (Ravikumar et al. 2010) and by inhibiting nuclear factor-jB (NF-jB) signaling which represses inflammation and cell proliferation (Salminen et al. 2011). Notably, AMPK controls the cellular stress defence via a downstream network of signaling pathways, for example, cAMP-responsive element-binding protein (CREB), forkhead box O (FOXO), peroxisome proliferator-activated receptor-1a co-activator (PGC-1a), mammalian target of rapamycin (mTOR) and silent information regulator 1 (SIRT1) (Canto and Auwerx 2010). Dysfunctions in AMPK signaling are associated with several diseases including diabetes, obesity and cardiovascular diseases (Steinberg and Kemp 2009). AMPK is an important molecular target in the development of therapies for metabolic and neurodegenerative diseases (Steinberg and Kemp 2009; Zhou et al. 2009a; Fogarty and Hardie 2010). Currently, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and the clinically-used metformin are potent activators of AMPK (see below). Alzheimer’s disease (AD) is a progressive neurodegenerative disease which is characterized by the deposition of amyloid-b peptide-containing neuritic plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein (Querfurth and LaFerla 2010). However, the molecular details of AD pathogenesis still need to be clarified. Interestingly, AD is associated with several neuronal abnormalities in energy metabolism, for example, mitochondrial dysfunctions and decline in glucose uptake, and defects in cholesterol metabolism and Ca2+ homeostasis (LaFerla 2002; Mosconi et al. 2008; Martins et al. 2009; Galindo et al. 2010). Considering the properties of AMPK, all these deficiencies might be linked to potential functional defects in AMPK signaling (Fig. 1). Here, we will outline the potential role of AMPK function in respect to various aspects affecting AD pathogenesis.

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Functional role of AMPK in AD In addition to hypothalamic neurons, distinct AMPK subunits are widely expressed in different brain regions in both rodent and human brains (Turnley et al. 1999; Culmsee et al. 2001; Vingtdeux et al. 2011a). The a2 subunit is the predominant catalytic unit expressed in adult brain and spinal cord with the highest expression being localized within the neurons of cortex and hippocampus and the Purkinje cells in the cerebellum (Turnley et al. 1999). Astrocytes do not express any AMPK subunits under resting conditions but high levels of expression are present in activated astrocytes. The a1 subunit is robustly expressed in embryos, but its expression declines during development (Culmsee et al. 2001). Regulatory b1 and b2 subunits are commonly expressed in adult neurons; typically the expression of b1 subunit is stronger than that of b2 (Turnley et al. 1999; Culmsee et al. 2001). The expression level and distribution of the c1 unit are rather similar to that of the a2 subunit (Turnley et al. 1999). At the cellular level, in neurons the staining of a2, b1 and c1 subunits is more intense in the nuclei, whereas in astrocytes the a2 subunit is mainly localized in the cytoplasm (Turnley et al. 1999). These immunohistochemical studies emphasize that most of the AMPK subunits are constantly expressed in neurons and thus can be functionally activated, for example, in AD.

AMPK regulates tau phosphorylation Tau protein, a major microtubule-associated protein, is a key structural and functional component in neuronal microtubules, particularly in those within axons. The phosphorylation of Ser/Thr residues is the main modification, which regulates the binding of tau to the tubulin protein in microtubules. However, abnormal hyperphosphorylation of tau can trigger the self-assembly of tau proteins into paired helical filaments (PHFs) and subsequently induce the fibrillization of PHFs into deposits of neurofibrillary tangles and ultimately cause a tauopathy (Iqbal and Grundke-Iqbal 1991; Buee et al. 2000; Alonso et al. 2001; Sengupta et al. 2006; Mandelkow et al. 2007). The phosphorylation status of tau is regulated by diverse protein kinases, for example, glycogen synthase kinase-3b (GSK3b), cyclin-dependent kinase 5 and microtubule-affinity regulating kinase, and protein phosphatases, such as PP2A and PP5. The site-specific phosphorylation of tau protein can also impede the intracellular trafficking of proteins along the microtubules and direct them to the degradation by proteasomal and lysosomal systems. Recently, Thornton et al. (2011) and Vingtdeux et al. (2011a) have demonstrated that recombinant AMPK phosphorylates tau protein at numerous sites in the microtubulebinding domain and within the flanking regions. Thornton et al. (2011) also verified that the AMPK-induced phosphor-

ylation inhibited the binding of tau to microtubules. Several of the phosphorylation sites were common to microtubuleaffinity regulating kinase 4 and GSK3b but also some unique sites to either of the kinases were shown to exist. They also reported that exposure of mouse cortical neurons to amyloidb(1-42) activated AMPK via Ca2+-dependent stimulation of CaMKKb. This indicates that Ca2+ dysregulation may have an important role in AMPK activation and subsequently in tau hyperphosphorylation. Vingtdeux et al. (2011a) demonstrated that there was abnormal accumulation of activated AMPK, that is, phosphorylated AMPKa2 (p-AMPK), in the cytoplasm of cerebral neurons in several tauopathies, such as AD and frontotemporal dementia with parkinsonism linked to chromosome 17. Immunohistochemical staining of AD brain samples revealed that p-AMPK was located in (i) granular structures resembling hyperphosphorylated, pretangle aggregates and (ii) tangle-like structures, similar to neurofibrillary tangles. Comparable stainings have been observed in frontotemporal dementia with parkinsonism linked to chromosome 17 tauopathy indicating that the activation of AMPK is associated with tau pathology and it is independent of amyloid-b deposition. In control brains, p-AMPK was predominantly localized into the nuclei in neurons suggesting that the translocation of activated AMPK from the nuclei to cytoplasm could trigger tau phosphorylation. These observations indicate that the activation of AMPK may precede the accumulation of hyperphosphorylated tau and tangle formation. Min et al. (2010) demonstrated that the acetylation of tau protein could inhibit its degradation and contribute to the appearance of tauopathy. They observed that the acetylation level of tau protein was clearly increased in human AD brains and the appearance of acetylation apparently preceded the hyperphosphorylation of tau and tangle formation. They reported that SIRT1 reduced the acetylation of tau and prevented the accumulation of phosphorylated tau proteins. Min et al. (2010) also presented evidence that the acetylation of tau blocked the ubiquitination of tau protein and its proteasomal degradation which enhanced the appearance of tauopathy. Interestingly, Julien et al. (2009) demonstrated that the expression of SIRT1 was clearly reduced in AD brains and that this decrease correlated with the accumulation of PHFs and the decline in cognition occurring before death. As described above, AMPK is a potent activator of SIRT1 and thus AMPK could enhance the proteasomal degradation of tau and prevent the appearance of tauopathy. In support of a role for AMPK in the inhibition of tau phosphorylation, Greco et al. (2009a) demonstrated that leptin reduced the level of tau phosphorylation by activating AMPK in rat cortical neurons. Treatment with AICAR, a potent activator of AMPK, also inhibited tau phosphorylation. In a subsequent study, the same authors revealed that AMPK was able to inhibit GSK3b activity and thus prevent the phosphorylation of tau protein (Greco et al. 2009b). It seems

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that the effect of AMPK on tau phosphorylation is contextdependent, that is, under certain conditions AMPK can directly phosphorylate tau protein, but in other instances AMPK is able to inhibit tau phosphorylation and aggregation through the activation of SIRT1 and the inhibition of GSK3b.

AMPK regulates amyloidogenesis A number of studies have indicated that AMPK can repress amyloidogenesis in neurons (Greco et al. 2009a; Lu et al. 2010; Vingtdeux et al. 2010; Won et al. 2010). It seems that AMPK activation is able to reduce amyloid-b peptide production in neurons through many different mechanisms. Won et al. (2010) demonstrated that the activation of AMPK with AICAR decreased the b-cleavage of amyloid-b peptide precursor protein (APP) in cultured rat cortical neurons. They did not observe any changes in the expression levels of APP and b-amyloid converting enzyme 1 (BACE1) or in the activities of a- and b-secretases. However, they detected that AICAR treatment clearly reduced the level of APP in lipid rafts. In contrast, no alterations in BACE1 levels or b-secretase activity were observed in lipid rafts. Moreover, they demonstrated that amyloid-b production was increased in mouse AMPKa2 knockout neurons and this correlated with the higher level of APP in lipid rafts. Won et al. (2010) also demonstrated that the activation of AMPK reduced the level of sphingomyelin in neuronal lipid rafts, that is, AICAR treatment decreased and the knockout of AMPKa2 increased the level of sphingomyelin in lipid rafts. It is known that lipid components affect the amyloidogenic processing of APP in lipid rafts (Vetrivel and Thinakaran 2010). There are clear disturbances in sphingomyelin metabolism in AD, which could affect protein translocation and enzyme activities in neuronal lipid rafts (Haughey et al. 2010). There are several studies indicating that AMPK can regulate the expression levels of a- and b-secretases and thus affect APP processing. Lu et al. (2010) observed that quercetin, a flavonoid, was able to activate AMPKa1/a2 by reducing the expression of PP2Ca, the major AMPK phosphatase. They demonstrated that via AMPK activation quercetin reduced the expression of BACE1, amyloid-b production and deposition of amyloid-b in the brains of mice fed with a high-cholesterol diet. It is also known that SIRT1, a target gene for AMPK activation, can suppress amyloid-b production by increasing the expression of disintegrin and metalloproteinase domain-containing protein 10 (Donmez et al. 2010), the a-secretase present in primary neurons (Kuhn et al. 2010). Increased expression of SIRT1 reduced the production of amyloid-b and amount of plaques in APP/ presenilin 1 (PS1) transgenic mice. Vingtdeux et al. (2010) demonstrated that resveratrol stimulated AMPKa1/a2 via the CaMKKb activation and subsequently reduced amyloid-b production, similar to AICAR treatment and transfection of

the constitutively active form of AMPKa1. They observed that resveratrol stimulated autophagocytosis, which facilitated the clearance of intracellular amyloid-b in HEK293 cells. Treatment with lysosomotropic drugs inhibited autophagic degradation and increased the intracellular level of amyloid-b in the presence of resveratrol. Recently, the same authors have screened novel small-molecule activators of AMPK which can enhance autophagy and promote intracellular amyloid-b degradation (Vingtdeux et al. 2011b).

AMPK and autophagy in neurons AMP-activated protein kinase signaling is one of the major regulators capable of activating autophagy (Ravikumar et al. 2010). AMPK activation inhibits mTOR, the main inhibitor of autophagy. Recently, it was demonstrated that AMPK can directly activate ULK1 (unc-51-like kinase), the mammalian autophagy-initiating kinase (Lee et al. 2010b; Kim et al. 2011). Autophagic uptake of cellular components has been linked to lysosomal degradation system through three pathways: (i) macroautophagy, mostly for larger structures, for example, mitochondria, (ii) microautophagy, and (iii) chaperone-mediated autophagy, in which cellular chaperones assist the uptake of proteins directly into lysosomes. Autophagy was discovered over 40 years ago (Arstila and Trump 1968) but its significance in cellular physiology and pathology has been clarified only during the last 10 years (Ravikumar et al. 2010). Autophagy has an important role in the regulation of aging and several age-related degenerative diseases, that is, conditions, in which there appear to be disturbances in the maintenance of proteastasis (Levine and Kroemer 2008; Eskelinen and Saftig 2009; Salminen and Kaarniranta 2009a; Ravikumar et al. 2010). Nixon and his collaborators have described disturbances in the endosomal-lysosomal system of neurons in AD since 1996 (Cataldo et al. 1996; Nixon and Yang 2011). They observed that there was an abundant accumulation of autophagic vacuoles, in particular in pyramidal neurons in hippocampus and prefrontal cortex. The autophagosomes and late autophagic vacuoles markedly accumulated in dystrophic axons and dendrites. Moreover, they were enriched in APP and b-cleaved APP, thus creating a major pool of intraneuronal amyloid-b (Yu et al. 2005). Later on their studies indicated that macroautophagic uptake was constitutively active, but the autophagic pathology in AD was attributable to impaired clearance of autophagic vacuoles (Boland et al. 2008). Surprisingly, Lee et al. (2010a) demonstrated that the AD-associated PS1 protein was an important carrier protein of v-ATPase V0a1, a proton pump protein, from endoplasmic reticulum to lysosomes. Knockout of PS1 protein prevented the delivery of the proton pump protein which induced a defect in the acidification of autophagic vacuoles and impaired proteolysis and clearance of vacuoles. Interestingly, they also demonstrated that

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fibroblasts carrying the AD-associated PS1 mutations also displayed disturbances in the acidification of accumulating autophagic vacuoles. Recently, Neely et al. (2011) demonstrated that the function of PS1 in autophagic clearance was not dependent on c-secretase activity. The role of PS1 in AD pathogenesis may be more versatile than initially thought, since different PS1-dependent functions could be altered in AD, for example, c-secretase activity, autophagy, and Ca2+ homeostasis (Parks and Curtis 2007; Zhang et al. 2010a). In addition, PS1 has many interacting proteins that may regulate its function, for example, the AD-associated ubiquilin-1, which directs its traffic to aggresomes (Viswanathan et al. 2011). Aggresomal targeting of PS1 did not affect c-secretase activity, but it is not yet clear whether other PS1-dependent functions are affected (Viswanathan et al. 2011). It seems that autophagy does not significantly alter amyloid-b production (Boland et al. 2010), but its deficiency in AD can have profound effects on neuronal function and susceptibility to apoptosis. Several studies have indicated that autophagy inducers, either AMPK activators or mTOR inhibitors, have beneficial effects on the pathogenesis in AD transgenic mice (Spilman et al. 2010; Vingtdeux et al. 2010; Yang et al. 2011).

AMPK and Ca2+ dysregulation in AD There is a substantial amount of literature highlighting that Ca2+ homeostasis of neurons is dysregulated in AD (LaFerla 2002; Bojarski et al. 2008; Yu et al. 2009; Zhang et al. 2010a). Khachaturian (1994) was the first to present the Ca2+ hypothesis in AD pathogenesis. Consequently, a large amount of data has supported this theory and it seems that disturbances in neuronal Ca2+ homeostasis trigger signaling pathways leading to many pathological responses that enhance AD pathology. For instance, Ca2+ can regulate APP processing and increase amyloid-b production which subsequently increase the intracellular Ca2+ concentration. Moreover, PS1 regulates the Ca2+ balance in endoplasmic reticulum and familial AD mutations disturb this regulation in hippocampal neurons (Zhang et al. 2010a). In addition, the presence of Ca2+ can increase the phosphorylation of tau by activating cyclin-dependent kinase 5 (Patzke and Tsai 2002). Furthermore, Ca2+ can cause tau dephosphorylation via stimulating calcineurin (Gong et al. 1994). All in all, Ca2+ is a crucial regulator in neuronal physiology, for example, in the maintenance of synaptic plasticity and learning and memory functions, and therefore dysfunction in Ca2+ regulation can augment AD pathogenesis. Ca2+ is a potent activator of AMPK via the activation of CaMKKb (Hawley et al. 2005; Woods et al. 2005). CaMKKb is highly expressed in mouse brain, in particular in hippocampal pyramidal cells and cortical layers 2 and 4–6 (Vinet et al. 2003). Neurons are sensitive to energy supply and increased neuronal activity regulates glucose uptake via

Ca2+-dependent activation of AMPK. The activation of kainate and NMDA receptors stimulates AMPK (Lee et al. 2009; Terunuma et al. 2010) and this consequently can enhance neuronal metabolism. In addition to metabolic activation, pathological disturbances in Ca2+ balance activate AMPK whereas chronic activation of AMPK can trigger neuronal cell death, either via the apoptotic or autophagic pathways. With respect to AD, Thornton et al. (2011) demonstrated that amyloid-b(1–42) exposure activated AMPK and induced hyperphosphorylation of tau in mouse cortical neurons. Tau phosphorylation was inhibited by memantine and a specific CaMKKb inhibitor indicating that increased intracellular Ca2+ levels stimulated AMPK via CaMKKb activation. Alzheimer’s disease is associated with cerebral amyloid angiopathy (Attems and Jellinger 2004). Deposition of amyloid-b to cerebral capillary walls induces local hypoxia and microhaemorrhages and even small local infarcts (Murray et al. 2007; Love et al. 2009). Several age-related neurological diseases, for example, AD and stroke, are associated with hypoxic stress (Ogunshola and Antoniou 2009; Zhang and Le 2010). Hypoxic stress disturbs the energy metabolism and Ca2+ balance and stimulates signaling pathways leading to the activation of hypoxia-inducible factor-1a (HIF-1a). For example, Hui et al. (2006) demonstrated that Ca2+ signaling stimulated the expression of HIF-1a protein during hypoxia. It is known that hypoxia facilitates AD pathogenesis through the up-regulation of BACE1 expression (Sun et al. 2006). Zhang et al. (2007) demonstrated that HIF-1a was involved in the activation of BACE1 and subsequently increased amyloid-b production. Recent studies have revealed that AMPK is the key regulator of HIF-1a function in hypoxia by stabilizing HIF-1a protein and thus stimulating its transcriptional activity (Lee et al. 2003; Jung et al. 2008). However, there are conflicting results indicating that in some experimental models, the activation of HIF-1a can be neuroprotective, but in others detrimental (Vangeison et al. 2008; Ogunshola and Antoniou 2009). There are several studies indicating that AMPK can trigger cell death pathways if the insult is overwhelming or is converted to a chronic stress condition, for example, in hypoxia or other Ca2+-associated pathological conditions (Li and McCullough 2010; Mazure and Pouyssegur 2010).

AMPK, metabolic and inflammatory disorders and AD Recent epidemiological studies have revealed that many metabolic diseases, including obesity, diabetes, hypercholesterolemia and several cardiovascular diseases, are risk factors for cognitive impairment and sporadic AD (Bhat 2010; Frisardi et al. 2010; Panza et al. 2010). This association has been termed metabolic-cognitive syndrome (Frisardi et al. 2010). Moreover, several lifestyle factors are linked to the

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development of AD, for example, smoking, physical activity, education and cognitive stimulation, alcohol and dietary factors (Flicker 2010). Bearing in mind that AMPK is the major regulator of cellular and whole-body energy balance, including glucose and lipid metabolism and mitochondrial biogenesis (Hardie 2008; Lage et al. 2008), it is tempting to speculate that AMPK is the crucial link between the metabolic disorders and sporadic AD. It is not known whether these pathologies are caused by the same mechanisms, for example, a deficiency in the AMPK activation, or if there is a causal association through the development of cerebrovascular diseases. However, there are many similar pathological characteristics associated with the AMPK abnormalities which are present in both diseases. These include (i) mitochondrial dysfunction, which is a crucial factor in both AD (Galindo et al. 2010; Swerdlow et al. 2010) and metabolic syndrome (Ren et al. 2010), (ii) disturbances in cholesterol and lipid metabolism and APOEe4 as a risk allele for both diseases (Olivieri et al. 2007; Martins et al. 2009; Bhat 2010) and (iii) increased endoplasmic reticulum (ER) stress and inflammatory disorders (Salminen et al. 2009; Dong et al. 2010; Hotamisligil 2010). Moreover, aging is a risk factor for both AD and the metabolic syndrome. There are several observations that the aging process inhibits or blocks the activation capacity of AMPK after insults, including stroke (Liu et al. 2011). An age-related decline in AMPK activation could be a common underlying factor for both diseases, although there can be a causal basis, for example, increased fatty acid levels can inhibit AMPK activity (Wu et al. 2007; Ko et al. 2009). A low-grade inflammation is a common attribute for AD, obesity and the metabolic syndrome (Heneka and O’Banion 2007; Hotamisligil 2010). There is extensive literature indicating that the activation of AMPK signaling inhibits inflammatory reactions via the suppression of NF-jB system through different pathways (Salminen et al. 2011). AMPK can regulate inflammation via (i) activating SIRT1, which inhibits NF-jB signaling (Yeung et al. 2004; Canto et al. 2009), (ii) stimulating FOXO proteins, for example, FOXO3a and FOXO4, which inhibit NF-jB signaling and prevent inflammation (Lin et al. 2004; Greer et al. 2007; Zhou et al. 2009b) and (iii) inhibiting ER stress and reducing oxidative stress, which subsequently repress NF-jB signaling (Terai et al. 2005; Li et al. 2009; Hotamisligil 2010; Wang et al. 2010). Many of these downstream targets also regulate neuronal survival, for example, SIRT1 can inhibit amyloidogenesis (Donmez et al. 2010), trigger autophagic degradation (Lee et al. 2008) and prevent the effects of oxidative stress (Chong and Maiese 2008). These studies indicate that cellular survival, energy metabolism and innate immunity responses all may well be coordinated through AMPK signaling. Some cytokines, for example, adiponectin, leptin and interleukin-6 (IL-6), act as activators of AMPK (Ruderman

et al. 2006; Lage et al. 2008). Leptin has several neuroprotective effects in AD, as will be described below. Adiponectin is released from adipose tissue and its concentrations are prominently increased in plasma and CSF in patients with mild cognitive impairment or AD (Une et al. 2011). The significance of the increased levels of adiponectin in brain function still needs to be clarified. IL-6 is a versatile cytokine, which has pleiotropic functions also in the brain (Spooren et al. 2011). It is an inflammatory cytokine supporting astro- and microgliosis but it is also a neurotrophic factor enhancing neuronal survival, neurogenesis and neuronal regeneration. The level of IL-6 is significantly increased in the serum of AD patients, as revealed by metaanalysis (Swardfager et al. 2010). Ko et al. (2009) demonstrated that in mouse heart, nutrient stress increased inflammation and IL-6 levels and decreased AMPK activity. An acute infusion of IL-6 significantly decreased the AMPK activity and reduced glucose uptake. Yang et al. (2010) observed that both inflammatory stimuli and a fatty acid-rich diet decreased the expression and activity of AMPKa1 in mouse adipose tissue and macrophages. In liver, endotoxin exposure blocks the expression of AMPK as well as that of SIRT1 (Zhang et al. 2010b). In contrast, in skeletal muscle, acute exercise induced IL-6 expression, which activated AMPK and increased glucose uptake (Ruderman et al. 2006). It seems that chronic inflammation represses the expression and activation of AMPK and may be involved in the development of the metabolic syndrome. It needs to be clarified whether chronic low-grade inflammation is able to decrease AMPK signaling in AD neurons and in that way suppress glucose uptake and increase amyloidogenesis.

Therapeutic modulation of AMPK activity and AD pathology Metformin and AICAR Metformin is a clinically used antidiabetic, a biguanide-type of drug, which activates AMPK by increasing the AMP concentration. Metformin reduces blood glucose, cholesterol and triglyceride levels, but it has several other effects that are both AMPK-dependent and -independent (Steinberg and Kemp 2009). Kickstein et al. (2010) observed that metformin activated PP2A and subsequently reduced tau protein phosphorylation at the sites dependent on PP2A dephosphorylation, both in cultured neurons and in mouse brain. It is known that okadaic acid, an inhibitor of PP2A, strongly affects tau hyperphosphorylation and neurofibrillary tangle formation (Arendt et al. 1995). Kickstein et al. (2010) also revealed that the metformin-induced increase in PP2A activity was independent of AMPK, but was mediated by the dissociation of the inhibitory components from PP2A complex. In the light of this data, it seems that metformin could provide a potent therapy in tauopathies. However,

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Chen et al. (2009) demonstrated that metformin increased amyloid-b production by up-regulating the expression and activity of BACE1 both in vitro and in vivo, an effect that was AMPK-dependent. Interestingly, in combination with insulin metformin potentiated the suppressive effect of insulin on amyloid-b generation. This is in agreement with the proposal that metformin displays an insulin-sensing effect. In a recent clinical study, it was observed that insulin when combined with another antidiabetic drug clearly reduced the densities of neuritic plaques in the hippocampus and neocortical areas (Beeri et al. 2008). Whether the metformin therapy alone could reduce the risk of AD pathology in human patients is not known. Labuzek et al. (2010) demonstrated that metformin increased in an AMPKdependent manner the phagocytosis capacity and acidification of lysosomal/endosomal compartments in microglial cells. This resulted in the enhancement of amyloid-b clearance and inhibition of neuritic plaque formation. The increased acidification capacity also potentiated autophagic clearance in AD neurons. 5-Aminoimidazole-4-carboxamide ribonucleoside is an AMPK agonist and a commonly used AMPK activator in pre-clinical experiments. There are observations indicating that AICAR can reduce amyloid-b production (Won et al. 2010) and tau phosphorylation at sites that are affected in AD (Greco et al. 2009a) at least in cultured neurons. Moreover, AICAR also inhibits proinflammatory responses in glial cells by inhibiting NF-jB activation (Giri et al. 2004). As described above, these observations imply that AMPK activators may possess therapeutic value in AD. Leptin Leptin is an adipokine, which is produced mostly in the white adipose tissue. It not only regulates energy homeostasis, but also has several neuroendocrine, immune and metabolic functions (Dardeno et al. 2010). The major function of leptin is to regulate appetite through the hypothalamic neurons. However, there are leptin receptors in several tissues and although leptin can transduce signaling via many different pathways, it seems that AMPK signaling is crucial in the peripheral tissues enhancing glucose uptake and fatty acid oxidation. Leptin can pass across the blood-brain barrier and leptin receptors are widely distributed throughout the brain, for example, in hippocampus and neocortex in addition to the hypothalamic neurons. In the brain, leptin has many neuroprotective functions and it can support synaptogenesis and neurogenesis (Signore et al. 2008; Merlo et al. 2010). Recent studies have indicated that leptin can exert therapeutic effects in many neurodegenerative diseases, including ischemic stroke, epilepsy and Parkinson’s disease (Signore et al. 2008). There is emerging data that leptin may also have a therapeutic role in AD (Tezapsidis et al. 2009). Clinical studies have revealed that an increased plasma leptin level was associated with a lower incidence of dementia and AD

(Lieb et al. 2009). In transgenic AD mice, leptin administration profoundly reduced the pathology and improved cognitive performance of the animals (Greco et al. 2010). Greco et al. (2010) demonstrated that leptin treatment reduced the level of total amyloid-b and amyloid plaque deposition in TgCRND8 mice. Leptin treatment was thought to downregulate b-secretase activity since the decrease in the level of APP C99 C-terminal fragment correlated with that of amyloid-b. The phosphorylation level of tau also decreased in the transgenic mice. Greco et al. (2009a,b) have demonstrated that leptin treatment reduced amyloid-b production and tau phosphorylation in an AMPK-dependent manner in neuronal cultures. Marwarha et al. (2010) observed that the treatment of rabbit hippocampal slice cultures with 27-hydroxycholesterol significantly reduced the leptin level and clearly increased the levels of amyloid-b and phosphorylated tau protein. Furthermore, leptin treatment reversed these effects by decreasing the expression of BACE1 and the activity of GSK3b. Greco et al. (2009b) also demonstrated that leptin treatment reduced tau phosphorylation via the AMPK-dependent inhibition of GSK3b. These studies support the scenario where leptin activates neuronal AMPK, which inhibits amyloid-b production and tau phosphorylation. In addition, leptin can enhance glucose uptake and mitochondrial biogenesis. Currently, leptin therapy carries promising hopes for the treatment of both the metabolic syndrome and AD. Leptin replacement therapy has been used in several clinical trials, for example, for treating lipodystrophy and obesity (ClinicalTrials.gov, Dardeno et al. 2010). Recombinant methionyl human leptin (Metreleptin) has been injected subcutaneously once or twice a day, similarly as insulin to diabetic patients. Natural compounds Many natural compounds present in different foods can activate AMPK (Hwang et al. 2009) and there are some studies indicating that they can also regulate APP processing and tau phosphorylation in an AMPK-dependent manner. The response mechanisms are still unknown, but most likely their effects are not specific for AMPK signaling. However, these daily dietary ingredients could have profound effects on the prevention of metabolic and neurodegenerative diseases via the activation of AMPK. Kim et al. (2010) have extensively reviewed the effects of naturally occurring phytochemicals on the pathogenesis of AD. Recently, resveratrol, a polyphenolic stilbene present mainly in red grapes, has received considerable attention because of its beneficial effects in many pre-clinical studies for example, on cardiovascular diseases and AD pathology. Dasgupta and Milbrandt (2007) demonstrated that resveratrol stimulated AMPK both in cultured neurons and in mouse brain and it also enhanced neurite outgrowth and mitochondrial biogenesis in cultured neurons. Vingtdeux et al. (2010)

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showed that resveratrol activated AMPK via CaMKKb activation. They also observed that resveratrol decreased the levels of intracellular and secreted amyloid-b peptides in mouse primary neurons. In addition, they observed that resveratrol triggered autophagy by inhibiting mTOR via AMPK activation and subsequently increased the lysosomal degradation of amyloid-b peptides. Dietary supplementation with resveratrol also reduced the formation of amyloid plaques in transgenic AD mice (Karuppagounder et al. 2009). Quercetin, a flavonoid present especially in green and black tea, can activate AMPK by reducing the expression of PP2Ca (Lu et al. 2010), which is a well-known AMPKphosphatase (Davies et al. 1995). Lu et al. (2010) demonstrated that a high-cholesterol diet elevated the expression of PP2Ca and concurrently reduced the activity of AMPK in the brains of old mice. Quercetin supplementation decreased the expression level of PP2Ca and correspondingly activated AMPK. Interestingly, quercetin administration down-regulated the expression of BACE1 and simultaneously reduced the level of amyloid-b peptides and amyloid deposits in the brains of old mice fed with a high-cholesterol diet (Lu et al. 2010). Moreover, quercetin decreased the presence of inflammatory markers and improved the cognitive deficits of these old mice. Quercetin can also attenuate the cytotoxicity induced by amyloid-b(1–42) in rat hippocampal cultures (Ansari et al. 2009). Recently, Shimmyo et al. (2008a) demonstrated that many flavonols and flavones, that is, apigenin, kaempherol, morin, myricetin and quercetin, directly inhibit BACE1 activity by docking to the catalytic center of BACE1. They also confirmed that these flavonoids reduced amyloid-b secretion in rat cortical neurons. Berberine and curcumin are two traditional Chinese remedies, which are known to activate AMPK (Jeong et al. 2009; Kim et al. 2009). Berberine, a plant alkaloid, has been claimed to exert many beneficial effects on CNS disorders including AD, cerebral ischemia and mental depression (Kulkarni and Dhir 2010). For instance, Zhu and Qian (2006) demonstrated that berberine significantly ameliorated the impairment of spatial memory in a rat model of AD. Berberine can also repress proinflammatory responses induced by different inflammatory insults via the activation of AMPK signaling in macrophages (Jeong et al. 2009) and in that way suppress pathologies linked to AD and the metabolic syndrome. Many recent studies have revealed that curcumin, which is present in curry powder, has beneficial effects in AD (Hamaguchi et al. 2010) and metabolic diseases (Aggarwal 2010). Curcumin administration was able to inhibit amyloid-b deposition and tau phosphorylation in transgenic AD mice and improved their behavioral impairment (Hamaguchi et al. 2010). Curcumin can also repress amyloidogenesis by inhibiting BACE1 expression and attenuating the oligomerization of amyloid-b (Shimmyo et al. 2008b). In the future, it is important to clarify the

therapeutic potentials of these natural compounds, which regulate the activation of AMPK signaling, in AD and metabolic syndrome.

AMPK: ally or enemy in AD? A substantial amount of literature indicates that AMPK is a neuroprotective factor, especially against metabolic stress but also against endoplasmic reticulum and oxidative stress via its signaling connections to many survival factors, for example, SIRT1, FOXO, PGC-1a and p53 (Poels et al. 2009; Ronnett et al. 2009; Salminen et al. 2011). Several experimental approaches have indicated that metabolic disturbances are linked to the pathogenesis of AD (Merlo et al. 2010). For instance, a significant decline in brain glucose metabolism is an early diagnostic marker of AD (Mosconi et al. 2008). Given that AMPK is the major regulator of glucose uptake and glycolysis, it is evident that AMPK may have a significant role in the prevention of AD pathology. It is known that the expression levels of major glucose transporters, GLUT1 and GLUT3, are clearly decreased in AD (Liu et al. 2008). AMPK can stimulate glucose uptake by increasing the expression of glucose transporters and/or by translocating transporters to cell surface. The activation of AMPK, for example, via glutamate excitation, can stimulate glucose uptake into neurons by increasing the surface expression of GLUT3 (Weisova et al. 2009). Interestingly, several studies have indicated that neurons are insulin-resistant in AD and that their glucose uptake is decreased (de la Monte 2009; Bosco et al. 2011). The expression levels of insulin and insulin like growth factor-1 (IGF-1) proteins and their receptors as well as insulin receptor substrate-1/2 proteins are significantly reduced in AD brains (Frolich et al. 1998; Rivera et al. 2005; Moloney et al. 2010). These studies indicated that the insulin/IGF signaling pathway was clearly compromised and the neurons had become insulin-resistant in AD. However, AMPK signaling provides an alternative pathway to regulate glucose uptake. It seems that AMPK could be a major regulator of energy metabolism in neurons, whereas the role of insulin/IGF pathway could be more significant in the regulation of neuronal growth and survival. In addition to metabolic regulation, AMPK signaling has an important role in neuroprotection via its downstream signaling targets including SIRT1, PGC-1a, FOXO proteins and NF-jB (Salminen et al. 2011). Moreover, increasing body of evidence indicates that AMPK signaling can inhibit tau phosphorylation and amyloid-b production and that the activators of AMPK can repress the pathogenesis of AD in transgenic mice (see above). AMPK also has an important role in vascular protection, for example, reducing lipid accumulation and inhibiting inflammatory changes (Ewart and Kennedy 2011). AMPK plays an important role in lipid metabolism, since it can repress cholesterol synthesis and

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prevent the development of atherosclerosis (Ewart and Kennedy 2011). Moreover, activation of AMPK induces cholesterol efflux from vascular foam cells and alleviates atherosclerosis in APOE-deficient mice (Li et al. 2010b). This may be related to the ability of AMPK to up-regulate the expression of ATP binding cassette G1 protein (Li et al. 2010c). ATP binding cassette G1 mainly functions as a cholesterol transporter, but it has also been suggested to modulate subcellular distribution and proteolytic processing of APP in vitro (Tansley et al. 2007). However, this observation has been disputed later in animal experiments (Burgess et al. 2008). Cerebral amyloid angiopathy (CAA) is a typical pathological change in AD. Increased cholesterol accumulation and arteriosclerosis is associated with CAA (Thal et al. 2003). It seems likely that deficiency in AMPK activation might enhance the formation of CAA in AD. Emerging studies indicate that AMPK signaling can regulate lifespan, probably by improving general health (Curtis et al. 2006; Selman et al. 2009; Mair et al. 2011). Mair et al. (2011) demonstrated that the activation of AMPK can extend the lifespan of Caenorhabditis elegans via the inhibition of cAMP-regulated transcriptional co-activator-1 (CRTC-1)/CREB signaling. In accordance with this finding, they also showed that Ca2+/calcineurin signaling activated the CRTC-1-mediated CREB signaling and subsequently reduced the lifespan. On the other hand, it is known that CaMKKb, an activator of AMPK, can inhibit Ca2+/calcineurin signaling and thus enhance the effect of AMPK on CRTC-1 (Hashimoto and Soderling 1989). There is a wide-array of signals resulting in CREB activation and even a larger number of CREB target genes, but it seems that the CRTC-1/CREB pathway triggers only a narrow subset of genes. Furthermore, chronic activation of CRTC/CREB is linked to pathological changes, for example, insulin resistance, hyperglycemia and inflammation (Altarejos and Montminy 2011). Interestingly, Mair et al. (2011) demonstrated that the activation of the CRTC-1/CREB pathway markedly up-regulated the genes associated with ER stress. Notably, AMPK signaling is a potent inhibitor of ER stress (Terai et al. 2005; Dong et al. 2010) and it is known that excessive ER stress can enhance AD pathology (Salminen et al. 2009), metabolic syndrome (Hotamisligil 2010) and the aging process (Salminen and Kaarniranta 2009b). Moreover, the stimulation of CaMKKb activates AMPK, which consequently triggers autophagy via the inhibition of mTOR, a major inhibitor of autophagy (Hoyer-Hansen and Ja¨a¨ttela¨ 2007). The autophagic degradation capacity declines during aging (Salminen and Kaarniranta 2009a) and this could enhance pathological changes observed in AD (see above). Taken together, AMPK signaling appears to alleviate different types of stress and thus it may protect cells against pathological alterations related to AD and metabolic syndrome. There are several studies indicating that the activation of AMPK via phosphorylation significantly declines with aging

(Qiang et al. 2007; Reznick et al. 2007; Turdi et al. 2010; Liu et al. 2011). This seems to parallel many metabolic changes associated with the aging process, for example, the prevalence of AD, obesity and metabolic syndrome increases with aging. Deficient AMPK activation impairs energy metabolism, including mitochondrial respiration, glucose uptake, fatty acid oxidation and lipid metabolism. Patel and Brewer (2003) demonstrated that the neuronal glucose uptake in the response to glutamate and amyloid-b was blocked in old rats, probably reflecting a lack of AMPK activation. In skeletal muscle, age-related defect in AMPKa activation induces insulin resistance (Qiang et al. 2007). In brain, stroke evokes a strong activation of AMPK in young mice, whereas in old mice there appeared to be no activation (Liu et al. 2011). The mechanism of the failure of activation capacity of AMPK with aging is not known. One possible mechanism might be an increased AMPK dephosphorylation with aging. There are several protein phosphatases which can restrict the activation of AMPK by dephosphorylating Thr172, for example, PP2Ca (Sanders et al. 2007), PP2A (Wu et al. 2007) and Ppm1E (Voss et al. 2011). The suggested role of PP2A is interesting in terms of AD pathogenesis, since PP2A can dephosphorylate tau protein directly, but also inhibit AMPK, one of the tau kinases (see above). Wu et al. (2007) demonstrated that C2-ceramide inhibits AMPK signaling by inducing the activation of PP2A. Interestingly, Cutler et al. (2004) demonstrated that ceramide levels were extensively increased in the brain regions that are vulnerable to pathological changes in AD. Normal aging also increased ceramide levels in mouse brain. The authors also observed that amyloid-b and lipid peroxidation induced the accumulation of ceramides in neurons. Increased ceramide production has been linked to a variety of stresses and it can regulate many signaling pathways (Hannun and Luberto 2000). It seems plausible that the regulation of AMPK phosphatases, such as PP2A and PP2Ca, may have a crucial role in the aging process itself as well as in age-related degenerative diseases. There is a substantial amount of data demonstrating that the activation of AMPK can also have detrimental outcomes. Several studies have demonstrated that the inhibition of AMPK activity confers neuroprotection in stroke (McCullough et al. 2005; Li et al. 2007; Li and McCullough 2010). Li et al. (2007) observed a significantly decrease in infarct volume in mice deficient in AMPKa2, but not in those lacking AMPKa1, compared with their wild-type counterparts. Hypoxia and the activation of HIF-1a-dependent signaling is an important factor in stroke and also in AD (Bergeron et al. 1999; Ogunshola and Antoniou 2009). Mazure and Pouyssegur (2010) observed that a low level of hypoxia could induce HIF-1a-mediated autophagy via Bcl-2/ E1B 19 kDa-interacting protein 3 that supported cell survival. In contrast, severe hypoxia or nutrient depletion triggered the AMPK/mTOR-dependent autophagy, which evoked autophagic cell death. AMPK can also provoke

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apoptotic cell death by activating Bcl-2 homology domain 3-only protein, a member of the proapoptotic Bcl-2 family (Concannon et al. 2010). Prolonged stimulation of AMPK via the overactivation of glutamate receptors is known to induce Bcl-2 homology domain 3-only protein expression and trigger excitotoxic apoptosis. Interestingly, Li et al. (2010a) showed that acute treatment with metformin exacerbated stroke damage but chronic metformin treatment before stroke was neuroprotective. This suggests that moderate AMPK activation can induce a hormetic resistance against more severe insults, probably by regulating AMPK phosphatases. In support of this proposal, compound C, an inhibitor of AMPK, decreased stroke damage in young mice, but it had no effect in aged animals (Liu et al. 2011). Diet restriction is a potent activator of AMPK and this can also improve cognitive function. Dagon et al. (2005) compared the effects of mild energy restriction (up to 60% of normal) and severe restriction (up to 40% of normal) on neuronal functions. Severe diet restriction induced a stronger AMPK activation than the moderate one in mouse hippocampus. A low level of AMPK activation was associated with improved cognition, whereas higher activation elevated catecholamine levels, induced neuronal apoptosis and impaired cognition. Thus, it seems that the responses of AMPK activation are dependent on the duration and degree of AMPK activation, that is, AMPK confers neuroprotection in transient moderate insults, whereas a prolonged and stronger activation of AMPK during chronic and overwhelming insults are detrimental, as is postulated to occur in cerebral ischemia (Li and McCullough 2010).

Conclusions Metabolic disturbances are associated with the pathogenesis of AD. A decline in glucose metabolism and defects in mitochondrial function and cholesterol metabolism suggest that there may be deficiencies in AMPK signaling. Moreover, aging is the major risk factor for AD, but is that associated with the significant decrease in the responsiveness of AMPK signaling with aging? One obvious example of the parallel, AMPK-dependent changes between aging and AD is the impairment of autophagic capacity which disturbs the maintenance of cellular proteostasis. The aging process and AD also involve an increase in ER and oxidative stress and dysfunctions in Ca2+ homeostasis which could be induced by the decline in AMPK signaling. A large body of literature indicates that AMPK has many neuroprotective properties which can suppress the pathogenesis of AD, that is, AMPK can repress tau phosphorylation and amyloid-b production, increase autophagic clearance, and inhibit the inflammatory responses present in AD. Evidently, AMPK can repress and delay the appearance of early signs of AD pathology. Conversely, the responses of AMPK activation are dependent on the type of stimulation and the extent of activating stress.

Bearing this in mind, it seems that chronic and overwhelming stress, such as is present in aging and AD, can evoke the detrimental properties of AMPK signaling. The accumulation of phosphorylated AMPK into the pre-tangled tau aggregates (Vingtdeux et al. 2011a) could be a reflection of the presence of chronic, excessive stress in AD neurons which subsequently might provoke tau phosphorylation and amyloidogenesis. AMPK signaling has all capacities to function as an effective brake of this vicious cycle and rescue neurons from degeneration, but in the case of unavoidable stress, it can trigger a cell death program. Taken together, it seems that the AMPK signaling network may be an important player in AD pathogenesis (Fig. 1).

Acknowledgements This study was financially supported by the grants from the Academy of Finland, the EVO-grant 5772708 from Kuopio University Hospital and the strategic funding for UEF-Brain consortium from the University of Eastern Finland, Kuopio. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript.

Disclosure of potential conflicts of interests The authors declare no conflicts of interests related to this work.

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