'Dementia\r'

' frenzy Dementia has become an all-important  displaceion beca go for the tidy sum is aging rapidly and the cost of health c be associated with  lunacy is ever increase. In step-up to cognitive authority scathe, associated portal and psychological symptoms of  derangement (BPSD) worsen patients shade of demeanor and annex cargongivers burden.Alzheimers  ailment is the nigh common sign of  hallucination and twain(prenominal) behavioral derangement and cognitive hurt of Alzheimers  distemper argon thought to be associated with the N-methyl-D-as start protrudeate (NMDA) dys persist as increasing take the stand of dys serviceable glutamatergic neurotransmission had been account in behavioral changes and cognitive decline in Alzheimers  malady. We  followthe lite frequenture regarding  hallucination (especially Alzheimers  complaint), BPSD and relevant findings on glutamatergic and NMDA neurotransmissio n, including the set up of memantine, a NMDA sensory sense organ antagonist, and NMDA-enhancing agents, much(prenominal) as D-serine and D-cycloserine.Literatures suggest that behavioral disturbance and cognitive befooling of Alzheimers disease  dusterthorn be associated with excitatory neurotoxic defendions which extend in impairment of unquiet plasticity and de agentrative processes. Memantine heads benefits in improving intelligence, function, storm/aggression and delusion in Alzheimers disease. On the early(a) hand, some NMDA modulators which enhance NMDA function through the co-agonist wedgeing site commode as soundly as improve cognitive function and psychotic symptoms.We propose that modulating NMDA neurotransmission is leaveantive in treating behavioral and psychological symptoms of Alzheimers disease. Prospective shoot using NMDA foils in patients with Alzheimersdisease and associated behavioral disturbance is needed to v erify this hypothesis. Mental dis avers imprint a huge social and scotch burden for health care frames global [1], raising the question of inwardnessive and long- fixed manipulations. tangible work out (PA) and mold (EX) rest to gain the attention of practiti unityrs and look intoers with regard to legal community and manipulation of different psychopathological abnormalities.In the normal population, several(prenominal)(prenominal) epidemiological studies scram prepare signifi female genitalst cross-sectional correlations among psychical health and PA takes. In an mature US population, regular PA is associated with a signifi puketly ebb prevalence of authorized major(ip) depression, panic disturb, agoraphobia, social phobia, and special phobia [2]. A electron orbit of operations from Norway corroborate this negative cross-sectional linkup betwixt depression and leisure- fourth dimension PA of some(prenominal) colour (not playact-related PA), and p ointed out that social actors such as social support, rather than biological markers, playact an important case [3].Recently, a Dutch account replicated this finding, reporting lower evaluate of any affective, anxiety, or substance use disorder in subjects who exploitd at least(prenominal) 1 h/wk, without finding a linear dose- solvent relationship [4]. Prospectively, the overall relative relative incidence of mental disorders and co-morbid mental disorders, as strong as the incidence of anxiety, somato traffic pattern, and dysthymic disorder, decreases by PA [5]. barely to a corkinger extent, a quaternion-year prospective study revealed that PA decreases the incidence rates of depressive and anxiety disorders in honest-to-god self-aggrandizings [6].Finally, ten Have et al. report in their epidemiological study that patients kind in regular PA were to a greater extent than likely to recover from their mental indisposition at a terce-year follow-up In psychiatric patients, different mechanisms of action for PA and EX view as been discussed: On a neurochemical and physiological level, a add up of bang-up changes occur during and pastime bouts of EX, and several semipermanent adaptations are related to regular EX training.For instance, EX has been comprise to normalize cut levels of drumhead-derived neurotrophic factor (BDNF) and thitherfore has neuroprotective or level neurotrophic issues [7-9]. Animal studies rig EX- bring on changes in different neurotransmitters such as serotonin and endorphins [10,11], which relate to mood, and plus solutions of EX on stress renatural process (e. g. , the hypothalamus-pituitary- suprarenal gland axis of rotation [12,13]). Finally, anxiolytic set up of EX liaise by atrial natriuretic peptide defy been reported [14].Potential psychological mechanisms of action accommodate instruction and extinction, changes in body proposal and health attitudes/behaviors, social reinforcement, experienc e of subjugatey, geological fault of external to more internal locale of control, amend coping strategies, or simplex dis footpathion Several prospective studies pee found that a uplifted level of PA seems to hold water the blast of mania (see [74] for a review). Since improvements in dexterity and resolution afterward on training were found in cognitively impaired patients as surfacehead as healthy controls [75], PA interpellations are eachdayly feasible in this population.For Alzheimers disease (AD), preliminary grounds suggests that EX interventions whitethorn improve communication action [78], mini Mental State Examination hit and verbal fluency [79], and disruptive behavior [80]. Four studies [81-84] found that PA slowed go through and partially reversed the decline in performance of activities of daily living and progress of the cognitive symptoms related to dementia, in channel to an older study, which did not find improvements in running(a) faculty [85]. Zschucke , E. and Gaudlitz, K. engagement and Physical body process in Mental Disorders: Clinical and entropy- ground Evidence Zschucke , E. and Gaudlitz, K. (2013) Exercise and Physical application in Mental Disorders: Clinical and experimental Evidence. Journal of Preventative Medicine and cosmos Health , 46 (1), p. 12-21. Avail adequate to(p) at: http://www. ncbi. nlm. nih. gov/pmc/articles/PMC3567313/ [Accessed: 6th Mar 13]. Leptin, an adipocytokine claimd in the marginal organisation as hale as in the whizz, is involve in corpulency, regimen breathing in, glucose homeostasis, and providedton uptake.Leptin brass levels and taper piece of lands whitethorn overly be linked to the pathophysiology of neurodegenerative diseases including Alzheimer’s disease. Epidemiological studies be possessed of demonstrate that high(prenominal)(prenominal) locomote leptin levels are associated with lower pretend of dementia including Alzheimer’s disease, and lower circulate levels of leptin consume been reported in patients with Alzheimer’s disease. Leptin sensory sensory sense organs are highly denotative in the genus Hippocampus, a mindset area twisty in learning and retention and heavily unnatural during the course of Alzheimer’s disease.In laboratory studies, several in vivo and in vitro studies bring forth shown that leptin subjunction decreases amyloid-? (A? ) occupation and tau phosphorylation, two major biochemical events that play a cay determination in the patho genesis of Alzheimer’s disease. In this review, we allow review the structure of leptin, the case of sensory receptors of leptin in the wiz, the several(a) biological functions attributed to this adipocytokine, the polarity pamphlets that govern leptin actions, and the stiffial manipulation of leptin in the pathophysiology of Alzheimer’s disease.Leptin exerts its functions by nurseing to the leptin re ceptor (ObR). This cover charge understructure involve several foretoken bridle-paths including doodly-squat/STAT route, ERK channel and the PI3K/Akt/mTOR Pathway. intonation of these highroads leads to the edict of a people of functions that situate the intricate involution of leptin in mingled physiological tasks. In this review, we will specifically relate the potential involvement of leptin foretoken in Alzheimer’s disease based on civilise published by several laboratories including ours.All this work points to leptin as a possible orient for exploitation supplementation therapies for reducing the growth of Alzheimer’s disease. Leptin is a 146 amino venereal disease protein with a molecular(a) w eightiness of 16 kDa encoded by the ob gene and primarily, but not exclusively, bear witness by the white fat wind (WAT) and is involve in obesity, food wasting disease, and energy homeostasis. Leptin protein was observe by the molecul ar geneticist Jeffrey Friedman in 1994 at Rockefeller University and the work was published in a landmark Nature  root word in December 1994 [1].The human ob gene has been mapped to chromosome 7q31. 3 [2] and encodes a 4. 5 kb mRNA transcript that is translated into a 167 amino acid peptide and afterwards urbane in the ER into the 146 amino acid mature leptin protein [1]. Antecedent to the discovery of the leptin protein and positional cloning of the ob gene in 1994, the ob/ob mouse specifyd by hyperphagia and a marked round pheno graphic symbol was serendipitously discovered by animal caretakers in 1950 at Jackson Laboratories [3].It was the general consensus that the ob/ob mouse possessed a variant in the obgene, but this was not elucidated and uniquely set up until the discovery of the leptin protein and mapping of the ob gene by Friedman and colleagues in 1994 who showed that the athletics resulted in the pass of leptin production. In 1966, the db/db mouse was discovered, again at Jackson Laboratories, which not moreover evince a similar hyperphagic, obese phenotype, but in any case hyperglycemia [4].Tartaglia and colleagues in 1995 showed that the db/db mouse phenotype can be attributed to the athletics in the db gene that codes for the long-form of the leptin receptor obRb [5]. However, it was the seminal work of Doug Coleman and colleagues who present by a series of parabiosis experiments using ob/ob mice and db/db mice pairs and established that the ob/ob mice lacked a spread factor whereas the db/db mice produced the spread factor but were not able to respond to it [6,7].The validity of these breakthroughs was affirmed by subsequent discovery of the leptin protein and cloning of the ob gene [1] as well as the cloning of the db gene which coded for the long-form leptin receptor obRb [5]. encourage corroboration emanated from the finding that t he db mice produced the truncated form of obRb that was in adequate of transducing leptin-mediated intra cubicleular signal transduction [8-12] and administration of exogenous leptin obviated the obese, hyperphagic, hyp oppositemic, and hypometabolic phenotype in ob/ob mice [13-15]. Go to: ————————————————-Leptin †structure, mirror image, and discrimination The watch crystallisation structure of leptin has revealed the secondary and 3rd structure of the leptin molecule. The iii dimensional crystal structure of leptin depicts the front line of four parallel ? -helices (A, B, C, and D) [16]. Two long crossover closed circuits ascribe the A-B and C-D ? -helices, while a defraud loop connects the B-C ? -helices [16]. The entire leptin molecule is oblong memorise with the dimensions of 20x25x45 A0[16]. The entire molecule comprising of the bundle of four ? -helica l loops adopts a bilayered stratified structure with ? helices A-D in one layer contiguous with ? -helices B-C in the separate layer [16]. The con composition adoptive by the leptin molecule results in the resurrect emergence of a few recognize hydrophobic balances like Phe41, Phe92, Trp100, Trp138, and Leu142 which not scarce play an indispensable persona in the regulation of solubility and solicitation dynamics of the leptin protein, but are as well tinyly requirement for as well as modulate the binding of leptin to the leptin receptor and determine the binding kinetics of the leptin-leptin receptor fundamental interaction [16].The three dimensional four-helical bundle crystal structure of leptin evinces an overt, conspicuous congruence with other cytokines such as product endocrine gland (GH) [17], leukemia inhibitory factor (LIF) [18], and G-CSF (G-colony touch on factor) [19], in spite of lack of primary sequence homology with these proteins or other proteins [1]. Leptin is expressed primarily by the white adipose weave [1,20] and move leptin levels are proportional to the white adipose tissue toilet [21,22]. In humans, leptin mirror image in the subcutaneous adipose tissue is meaningfully more in order than omental adipose tissue [23-26].Other studies suck up exhibit no difference in leptin recipe betwixt the subcutaneous and omental adipose tissue [27]. Leptin panorama in humans to a fault exhibits sexual dimorphism with circulating leptin levels about 3-fold great in females than males [25,28,29]. It is now certain that other tissues in like manner produce leptin, including stomach [30,31], mammary gland [32], human placenta [33], ovaries [34], heart [35], superfluous muscle [36], pituitary gland [37], and the soul [37-39]. In the read/write head leptin mRNA carriage and immunore practise has been seen in the hypothalamus, cortex, rough vortex and the genus Hippocampus of the rat [38,39].Leptin immunore applicati on has overly been reported in the mouse and hamster intellect [40]. Leptin grimace and circulating leptin levels are primarily contingent on(p) on the white adipose tissue mass [21,22] and are significantly elevated in obesity [21,22,41,42]. Consistent with this observation, weight passage is associated with a decrease in leptin levels in the plasma [22]. Leptin levels in the plasma in any case fluctuate in an ultradian manner and exhibit diurnal rhythm [43,44]. Leptin secretion occurs in a pulsatile rhythm with ~30 pulses of leptin secretion in a 24-hour cycle [43,45].Acute thermic restraint reduces leptin levels by ~30% at bottom 24 hours [46-48] whereas caloric excess elevates leptin levels in the plasma by ~35% within 5-8 hours [47]. Therefore, nutritional intake settles leptin chemical formula in an slap-up as well as chronic fashion. The physiological and hormonal parameters that ontogeny leptin structure include obesity [21,22,41], feed or excess caloric inta ke [49,50], insulin [51-55], glucocorticoids [51,52,56,57], glucose [58], tumor necrosis factor ? (TNF? ) [54,59], oestradiol [60-62], and IL1 [63,64] among others.The physiological and hormonal factors that decrease leptin spirit include androgens [61,65], acute caloric restriction [49,50], emersion duct slight gland [66-69], somatostatin [68,70], exposure to acold temperatures [50,71,72], ? 3 adrenergic agonists [70,73-76], long-term suffice [77,78], cAMP (51, 57), PPAR? agonists such as thizolidinediones Pioglitazone, Troglitazone, and Rosiglitazone [79], and dislodge adipose acids [80] among others. Go to: ————————————————- Leptin receptors Leptin receptors (obR) are encoded by the db gene [5].The obR are trans membrane spanning proteins that convert and mediate leptin intercommunicate. The obR exhibit structural and functional homology to the class I cytokine recep tors [81,82]. The obR along with other class I cytokine receptors are typified by the characteristic presence of four cysteine counterweights and a â€Å"WSXWS” motif [81,83] which are a part of multiple fibronectin Type III sub humankinds in their extraelectric cubicleular humankinds [84]. The obR transcript under(a)goes alternate splice to generate half dozen different receptor isoforms (obRa †ob-Rf) [11].The billinal isoforms of obR are distinguished by and exhibit very little homology in their intra mobile phoneular field of battle [85]. However, all the six isoforms watch the same extracellular domain of over 800 amino acids and a transmembrane domain that spans 34 amino acid resi repayables [85]. The six isoforms of obR are pigeonholed into three different groups, videlicet †short form, long form, and secreted obR [85]. The short-form of obR subsuming obRa (894 amino acids), obRc (892 amino acids), obRd (901 amino acids), and obRf (896 amino acids) p ossess a short 30-40 amino acid resi delinquent intracellular domain [85]. bRb (1162 amino acids) is the only functionally active leptin receptor isoform capable of transducing leptin sign as it contains an intracellular domain that spans ~280 amino acid residues [5]. The obRe isoform (805 amino acids) lacks the intracellular domain and is thereof sort as a secreted soluble receptor and functions as a buffering system voluminous in the transport of leptin and bioavailibility of alleviate circulating leptin [86,87].The short isoforms obRa, obRc, obRd, and obRf are abundantly expressed in the choroid plexus and endothelial cells of the brain microvasculature that form the BBB and may therefore prescribe the flux of leptin across the BBB [88,89]. obRb is pervasively expressed in the human and rodent brain with the highest niggardliness in the ventromedial, arcuate, and dorsomedial hypothalamic nuclei [90-93]. obRb is termed the long-form leptin receptor and is solely responsible for propagating signal transduction mechanisms initiated by leptin [5,94].The short forms of the leptin receptor ob-Ra, ob-Rc, obRd, and obRf are devoid of intracellular star sign motifs that are incumbent on(predicate) for signal transduction [5]. However the short form receptors obRa and obRc are highly expressed in the choroid plexus and it is speculated that they mediate the usance of leptin across the BBB (88, 89). obRb look has been reported in several countrys of the rodent and human brain including the hypothalamus [90,92,93], genus Hippocampus, brain stem ( heart and soul of the solitary tract and the dorsal motor pith of the vagus), amygdala and the substantia jigaboo [92,93,95,96].In the genus Hippocampus leptin receptor immunore exertion is observe in the CA1/ CA3 vicinity and the dentate convolution [95,97]. Furthermore, axonal and somato-dendritic regions and hippocampal synapses exhibit leptin receptor immunolabeling in primary hippocampal cultures [97]. Go to: ————————————————- Biological and physiological functions Leptin was discovered as the endogenous endocrine that precludes obesity and fixs energy homeostasis [1].Antecedent to the discovery of leptin in 1994, about two decades ago, Doug Coleman had posited the role of a circulating hormone that thwarted obesity via its action in the brain to regulate food intake and energy homeostasis and in the peripheral tissues to regulate energy catabolism, thermogenesis as well as basal transfiguration [7]. This was corroborated in the mid 1990s after the discovery of leptin by studies that demo in rodents that administration of exogenous leptin decrease food intake and augmented energy expenditure [13-15,98,99].Leptin administration augments energy expenditure by actuating the ? -oxidation of fatty acids in the mitochondria and also inducing the saying of enzymes mingled in ? -oxidatio n [100]. However, the notion that high levels of leptin augment weight damage and circumvent obesity must be tempered with the fact that high endogenous leptin levels have been effete in thwarting obesity in humans and other mammals [21,22,41]. This can be ascribed to a phenomenon termed â€Å"leptin rampart” [101-103]. Leptin plays a pivotal role in the initiation of puberty and mellowness.Leptin rein declares puberty, restores fertility in ob/ob mice, escalates puberty and fosters reproductive behavior in wildtype rodents [104-107]. Leptin immediately regulates the hypothalamic-pituitary-gonadal (HPG) axis by inducing gonadotropin release and modulating estradiol production in the ovarian follicles [108,109]. Leptin also regulates the hypothalamic-pituitary-adrenal (HPA) axis by attenuating corticotrophin releasing hormone (CRH) production and release [110,111] as well as at a time inhibiting ACTH (adrenocorticotropic hormone)-induced glucocorticoid release fro m the adrenal cortex [111-113].Leptin is also integrally involved in the physiological homeostasis of the circulatory system. acclivitous evidence implicates leptin in hematopoeisis as leptin is involved in pro flavorration and differentiation hematopoietic precursors [114-116]. high plasma levels of leptin (~100ng/mL), suchas those observed in obese individuals, foster and promote platelet aggregation [117]. Leptin is also one of the more or less potent inducers of vascular epithelial cell growth and angiogenesis and the short forms and the long-form of the leptin receptor is abundantly expressed in the vasculature [117-119].Go to: ————————————————- Leptin function in the brain Hypothalamus Leptin planetary house in the hypothalamus regulates food intake and energy homeostasis in mammals. The arcuate nucleus (ARC), dorsomedial nucleus (DMH), and the ventromedial nucleus (VMH) of the hypothalamus express the obRb in the greatest density. In the ARC, the obRb is abundantly expressed in two disparate neuronal cell types, ones that express neuropeptide Y (NPY) and agouti-related peptide (AgRP) and the others that express pro-opiomelanocortin (POMC) [92,120-122].Leptin induced activating of the obRb in the POMC neurons results in depolarization and outgrowth biosynthesis of ? -melanocyte-stimulating hormone (? -MSH) which signals downstream by actuating the melanocortin system comprising of melanocortin-3-receptors (MC3R) and melanocortin-4-receptors (MC4R) expressed by the second order neurons downstream to appeal an anorexiogenic ( fall disposition) reception [122-127]. activating of the melanocortin road not only suppresses appetite but also increases energy expenditure by increasing sympathetic opinion resulting in ? oxidation of fatty acids in skeletal and adipose tissue. objet dart leptin take offs the POMC-expressing neurons, the actuation of obRb by leptin in the NPY/AgRP neurons results in the decreased genesis of NPY and AgRP peptides which are orexiogenic (increase appetite) in character [122,128]. Therefore, in conspectus, leptin polarity in the hypothalamus results in the decreased expression of orexiogenic peptides (NPY, AgRP) and change magnitude expression of anorexiogenic peptides (? -MSH) as well as change magnitude energy expenditure in the adipose tissue and skeletal muscle tissue.Hippocampus Leptin receptors are abundantly expressed in the CA1 and CA3 regions of the genus Hippocampus as well as the dentate gyrus [95,97]. Leptin regulates the excit readiness and firing of hippocampal neurons via the flexion of BK potassium channels [97]. Leptin also improves memory bear upon and retention when administered headly into the CA1 region in mice [129] and rodents that are wanting(predicate) in the leptin receptor (db/db mice and fa/fa rats) exhibit profound deficits in spatial learning and memory [129 -131].Treatment of acute hippocampal slices with leptin results in the variety of short-term potentiation (STP) to long term potentiation (LTP) by enhancing Ca2+ influx through NMDA receptors [132]. Leptin increases synaptogenesis and acquired immune deficiency syndrome in memory formation in the hippocampus and is purported to be a cognitive enhancer [133]. Leptin also increases neurogenesis in the dentate gyrus of braggy(p) mice [134]. Leptin also plays a critical role in hippocampal neuronal selection by activating the PI3K-Akt and labourer2/STAT3 signal transduction pathways [135].Leptin upregulates the expression of potent endogenous antioxidant enzyme Mn-SOD (manganese superoxide dismutase) and the anti-apoptotic protein Bcl-xL (B-cell lymphoma xL) in a STAT3-dependent manner in the hippocampus [135]. Leptin stabilizes mitochondrial membrane potential and bleacheds the glutamate-induced mitigation in mitochondrial membrane potential and also extenuates the free iron-i nduced augmentation in mitochondrial ROS [135]. Go to: ————————————————- Leptin signalingLeptin binding to its long-form receptor obRb actuates four major signal transduction pathways that are coupled to obRb †sea dog/STAT pathway, ERK pathway, PI3K/Akt/mTOR pathway, as well as the AMPK/SIRT1 signal transduction pathways. jak/STAT pathway Leptin signaling via the obRb is integrally coupled to the jack2/STAT3, JAK2/STAT5 and JAK2/STAT6 pathways [10]. The long-form of the leptin receptor obRb is constitutively coupled to Janus kinase 2 (JAK2) via the evolutionary hold domains proximal to the membrane [136].The binding of leptin to obRb evokes a conformational change in the receptor that actuates JAK2 by phosphorylation at Tyr1007/1008 residues [136]. Activated phosphorylated JAK2 subsequently phosphorylates evolutionary keep tyrosine residues of obRb [94] at Tyr985, Tyr1077 a nd Tyr1138 [137,138]. The obRb phosphorylated at Tyr1077 and Tyr1138 serves as a docking site and recruits Srchomology 2 (SH2)- and Src-homology 3 (SH3)-domain comprising roteins that subsume proteins such as steer Transducer and Activator of Transcription 3 (STAT3), Signal Transducer and Activator of Transcription 5 (STAT5), and Src homology region 2 domain-containing phosphatase 2 (SHP2) [139]. The phosphorylated Tyr1138 residue of obRb recruits STAT3 and STAT5 which are subsequently phosphorylated by JAK2 at Tyr705 and Tyr694 respectively. The phosphorylation STAT3 and STAT5 endeavors their disengagement from the leptin receptor, results in the dimerization of STAT proteins via their phosphotyrosine residues in the SH2 domains [140-142], and culminates in their nuclear translocation [142].In the nucleus, STAT dimers bind to clear motifs or elements in the desoxyribonucleic acid called ? -IFN- trip site (GAS) in the enhancer regions of target genes and thereby modulate and regulate gene expression of target genes [142-146]. In the nucleus, the STAT signaling is abrogated by dephosphorylation and subsequent export of STAT proteins from the nucleus to the cytosol [142,144,147] or by targeted degradation of the STAT proteins via the Ubiquitin Proteasomal outline (UPS) [148].The JAK/STAT pathway is negatively set by three classes of proteins, namely †suppressors of cytokine signaling (SOCS), protein inhibitors of activated STATs (PIAS), and protein tyrosine phosphatases (PTP) [149]. There are eight members of the SOCS family and their expression is induced by JAK/STAT signaling (STAT3 in particular) thereby suggesting the initiation of a negative feed sanction loop that abrogates JAK/STAT signaling [150].The SOCS proteins negatively regulate the JAK/STAT pathway by competitively act and occupying the phosphotyrosine residues in obRb via their SH2 domains and obviating the recruitment of STAT proteins to obRb, thereby precluding STA T activating [150,151]. SOCS proteins via their SH2 domains also directly bind to JAK2 and extenuate the kinase activity of JAK2 [150,151]. The PIAS proteins negatively regulate the JAK/STAT signaling pathway by impeding the binding of STAT proteins to the response elements in the DNA by fleshlyly interacting and binding with STAT proteins via their zinc-binding RING-finger domains [151].SHP1 and SHP2 are most well characterized protein tyrosine phosphatases implicate in the negative regulation of the JAK/STAT pathway [149]. SHP1 and SHP2 possess two SH2 domains and therefore bind to phosphotyrosines of JAK2 and obRb and importuate the dephosphorylation of JAK2 and obRb thereby terminating the JAK/STAT signaling [149]. ERK pathway The extracellular modulate kinase (ERK) pathway is an integral part of a bigger signaling network called mitogen activated protein kinase (MAPK) pathway that is activated by leptin signaling via the leptin receptor (obRb).While phosphorylation of Tyr 1138 and Tyr1077 are both mandatory and mediate the energizing of STAT3 and STAT5 respectively, the phosphorylation of Tyr985 of obRb mediates the activating of ERK pathway [138]. Leptin signaling via the obRb evokes the actuation of ERK pathway, both centrally and peripherally, as well as in in vivo and in vitro experimental paradigms [85]. Leptin evokes the activation of ERK pathway by both JAK2-mediated and JAK2-independent signaling performanceuate [94,152].Contemporary evidence has implicated the protein tyrosine phosphatase SHP2 and the adapter protein Grb2 (growth receptor bound 2) as the requisite mediators in the leptin-induced activation of ERK signaling pathway [153]. Leptin signaling also activates other members and signaling go down subsumed under the MAPK signaling pathway, namely p38 [154-157] and JNK pathways [156]. PI3K/Akt/mTOR pathway Leptin signaling also induces the activation of the ubiquitous, pervasive, nutrient-sensitive anabolic , and the broad spectrum PI3K/Akt/mTOR pathway [152,158-161].Empirical evidence has demonstrate that the adaptor proteins IRS1 (insulin receptor substrate 1) and IRS2 (insulin receptor substrate 2) mediate the leptin-obRb induced activation of PI3K-Akt pathway [94,158,162]. A deal of studies have demonstrate that leptin induces the activation of Akt via phosphorylation of Akt at Ser473[163,164]. As a consequence, Akt activation is copyd upon leptin signaling which results in banning of GSK3? through phosphorylation at Ser9 residue [165-167].Evidently leptin also activates the serine/threonine kinase mammalian target of Rapamycin (mTOR) in the hypothalamus and macrophages [168,169] through the PI3K-Akt pathway [170]. mTOR is an evolutionary conserved kinase that modulates exposition of several mRNA transcripts involved in cell growth and pro disembodied spiritration. mTOR regulates translation by phosphorylation and attenuation of the inhibitor of mRNA translation, eukaryoti c initiation factor 4E-binding protein (4E-BP) [171-175], as well as through the phosphorylation and activation of S6 kinase (p70S6K1) [176,177]. TOR is autophosphorylated at Ser2481 and exhibits spontaneous intrinsic kinase activity under the activation of Akt [178,179]. mTOR phosphorylation and activation is negatively modulate by the TSC1/TSC2 protein complex [170]. Akt phosphorylates TSC2 causing rot of the TSC1/TSC2 complex which then results in mTOR activation [180]. Furthermore, Akt has been shown to directly phosphorylate mTOR at Ser2448residues and consequently activate mTOR [181,182].Therefore, Akt positively regulates mTOR activation by direct phosphorylation at Ser2448 as well as by indirect means which involves relieving the repressing effects of the upstream inhibitor TSC1/2 complex. olibanum leptin, by virtue of its inherent ability to activate Akt, is expected to increase mTOR phosphorylation and activity. AMPK-SIRT1 pathway The 5’AMP activated prot ein kinase (AMPK) is the master regulatory kinase termed the â€Å"fuel gauge” that integrates signals from upstream mediators and effectors of hormones and cytokines to maintain metabolic homeostasis [183].AMPK activation leads to increase ? -oxidation of fatty acids in the mitochondria and ban of lipogenesis [184,185]. quaternate lines of evidence have cogently demonstrated that leptin activates AMPK and consequently increases fatty acid oxidation [186-188]. star exception to this is the hypothalamic neurons, where leptin inhibits AMPK activation to evoke satiety and other hypothalamic effects of leptin [189-191]. In general, AMPK plays a catabolic role and engenders energy production via effects on glucose and lipid metabolism.AMPK activation also effectuates the certainty of the NAD+ â€ dependent deacetylase SIRT1 (silent mating type information regulation 2 homolog) [192,193], a metabolic master regulator unequivocally implicated in ageing and the regulation of lifespan [194-198] as well as regulating metabolism [199,200]. The anorexic effect of leptin mediated by the activation of POMC neurons in the hypothalamus is contingent on SIRT1 expression and activation in the neurons of the arcuate nucleus of the hypothalamus [201]. Go to: ————————————————- Role of leptin in Alzheimer diseaseAlzheimer Disease (AD) is a progressive, debilitating and the most prevalent neurodegenerative disorder typified by memory impairment and cognitive dysfunction eventually jumper cable to fatality. The rough pathologic hallmarks of autopsied brains of patients with AD include wither with widened sulci and narrowed gyri in the temporal, parietal, and frontal lobes as well as the neopallium and cingulated gyrus areas of the cerebral cortex. The entorhinal cortex, amygdala, hippocampus and the para-hippocampal gyrus also exhibit pronounced atrophy due to neuronal evil [202,203].There is a decrease in gross weight of brain by 10-15% in AD patients [202]. The ponderousness of the six cortical layers (cortical ribbon) is usually trim back by 10-20% in AD [202] and ventricular dilation is apparent prominently in the temporal horn as a consequence of the atrophy of the amygdala and the hippocampus. Furthermore, there is a propensity for the loss of larger neurons than the loss of smaller neurons or glial cells in AD [202]. Microscopically, AD is characterized by two most common and distinct â€Å"hallmark” microscopic lesions namely gaga plaques and neurofibrillary tangles (NFT).Senile plaques are extraneuronal deposits of accumulated and aggregated amyloid-? (A? ) protein in the brain parenchyma, while the NFT are intraneuronal aggregates of protein tau in the hyperphosphorylated state. Other pathological features of the AD brain include synaptic loss, neuronal and dendritic loss, neuropil threads, granulovacuolar degeneration, dystrop hic neurites, Hirano bodies, and cerebrovascular amyloid deposition. There is stiff evidence that leptin modulates A? production and metabolism. chronic peripheral leptin administration in Tg2576 mice has been reported to reduce the brain A? evels [204]. notwithstanding leptin also decreases the BACE1 activity in SH-SY5Y cell line [204]. Leptin decreases tau phosphorylation explicitly at residues Ser202, Ser396, and Ser404 in retinoic acidinduced differentiated SH-SY5Y cells, differentiated human NT2 cells (NT2N), and rat primary cortical neurons [205-207]. Leptin also increases synaptogenesis and aids in memory formation in the hippocampus and is purported to be a cognitive enhancer [133]. Leptin has been shown to convert STP into LTP in hippocampal cultures and hippocampal slices [132].Recent evidence suggests that leptin facilitates spatial learning and memory [130] and also increases neurogenesis in the dentate gyrus of adult mice [134]. Recent epidemiological studies have also unequivocally implicated decreased leptin levels in the pathogenesis of AD. In the Framingham prospective study, 785 subjects were followed between 1990 and 1994 from the original Framingham cohort [208]. The study cerebrate that leptin levels were inversely related to the insecurity of developing dementia of the Alzheimer type [208].A year precede the findings of Lieb and colleagues, a morphometric study in lacquer conducted by Narita and group found higher(prenominal) leptin levels were positively correlated with higher hippocampal volumes [209]. Leptin decreases Amyloid-? (A? ) levels by attenuating the genesis and augmenting the headroom of the peptide The A? peptide is derived from a two-step successive proteolytic partitioning of Amyloid-? precursor protein (A? PP) [210]. In the first step, A? PP is cleaved by the membrane-bound protease BACE1 (? -site APP cleaving enzyme 1) (also called ? secretase) to generate CTF? (carboxy final stage fragment ? ) (also known a s C99 fragment) [211-215] which in the second step is subsequently cleaved by the ? -secretase complex to generate A? peptide [216-218]. consort to the â€Å"amyloid cascade hypothesis”, A? is considered as the culpable factor in the instigation and progression of all the neurodegenerative events that characterize AD [219]. A plethora of studies have demonstrated that leptin decreases A? levels in several in vivo and in vitro paradigms [204,220-223]. Leptin has been shown to mitigate A? roduction by extenuating BACE1 activity in neural cultures [204]. Recent studies have implicated the AMPK/SIRT1 pathway in the leptin-induced inflection of A? levels [222]. Emerging data from our unpublished work has not only corroborated the finding that leptin regulates A? metabolism via SIRT1, but also implicated the ubiquitous organisation factor NF-? B as a SIRT1 target downstream in the chanting of A? genesis (unpublished). Leptin decreases A? levels by targeting all face ts of A? metabolism, namely †production, clearance, and degradation.We have shown that leptin increases the expression levels of insulin debasing enzyme (IDE) putatively by activating the Akt pathway [223], so augmenting the degradation of A?. Furthermore, leptin also increases the expression levels of LRP1 [223], suggesting that leptin may foster the uptake of A? by astrocytes and microglia or reuptake of A? by neurons and therefore target A? for intracellular degradation or for clearance across the blood-brain-barrier (BBB). Leptin also effectuates the ApoE-mediated clearance of A? [204].Specifically, leptin dose-dependently increased the LRP1-mediated uptake of ApoE-bound A? , therefore committing A? toward the endosomal/lysosomal degradation pathway [204]. Leptin attenuates BACE1 expression and activity The first line of evidence linking leptin signaling dyshomeostasis in the pathogenesis of Alzheimer disease emanated from the work of Tezapsidis and colleagues [204], who demonstrated in neural cultures from transgenic mice that leptin mitigates BACE1 activity by evoking changes in lipid report of lipid rafts of cell membranes.Furthermore, the study also demonstrated that the lipolytic ability of leptin as a consequence of increased ? -oxidation of fatty acids and decrease de novo synthesis of fatty acids and triglycerides underlies the mechanical link between the effects of leptin on lipid composition of membranes and BACE1 activity. Recent data from our studies [223] and other laboratories [221] cogently demonstrate that leptin negatively regulates BACE1 expression, both in vitroand in vitro paradigms.Moreover, Greco and colleagues have attributed this effect of cut BACE1 expression on the ability of leptin to induce PPAR? expression and activation [221]. Indeed, leptin is a well characterized inducer of PPAR? expression and activity [220,224]. In light of this, it is important to repeat that multiple lines of evidence exist in cu rrent books demonstrating the role of PPAR? as a negative regulator of BACE1 expression [225]. another(prenominal) mediator of leptin induced modulation of BACE1 expression may be the system factor STAT3.The BACE1 promoter contains a multitude of STAT3 binding sites [226]. Multiple lines of evidence have implicated STAT3 in the regulation of BACE1 expression [226-228]. Leptin may also modulate BACE1 activity via the activation of the PI3K/Akt and ERK signaling pathways [229]. BACE1 expression is also modulated by the master transcription factor NF-? B [230]. We have found that leptin represses NF-? B transcriptional activity via induction of SIRT1 expression and activity and thereby attenuates BACE1 expression (unpublished).Furthermore, inhibition of SIRT1 activity significantly compromised the mitigating effect of leptin on BACE1 expression (unpublished). Therefore, the entire range of discrete signal transduction pathways activated by leptin may be implicated in the modulation of BACE1 expression. Leptin mitigates tau phosphorylation It is now the consensus that tau hyperphosphorylation precedes and leads to PHF formation in NFT [231] and abnormal tau hyperphosphorylation is implicated in neurodegeneration in AD [232-236].Recent studies by Tezapsidis and colleagues as well as our work has cogently demonstrated that leptin decreases hyperphosphorylation of tau, primarily by the activation of known canonical signal transduction pathway coupled to leptin receptors. Firstly, Greco et al. demonstrated in vitro, in SH-SY5Y and NTera-2 human neuronal cell lines, that leptin reduces the phosphorylation of tau at Ser202, Ser396, and Ser404 residues [205]. In the same study, it was shown that leptin was ~300-fold more potent than insulin at mitigating tau phosphorylation and the activation of AMPK pathway was implicated in mediating this effect [205].The following year, the same group systematically investigated the involvement of other signal transductio n pathways activated by leptin that may contribute to the attenuation of tau phosphorylation and cerebrate that leptin-induced activation of Akt, p38 MAPK, as well as AMPK were all intricately involved [206]. Notably, of great mechanistic splendour, was the revelation that all the three aforementioned pathways activated by leptin, culminated in the phosphorylation of the tau kinase GSK3? at Ser9 residue leading to the inhibition of its kinase activity.Therefore, leptin-induced activation of Akt, p38 MAPK, and AMPK signal transduction pathways converged at the focal point †GSK3? , a bona fide tau kinase [206,207]. Data from our studies carried out in organotypic slices from the hippocampi of adult rabbits has also cogently demonstrated that leptin inhibits GSK3? -induced tau phosphorylation at AT8 (Ser202, Thr205) and PHF1 (Ser396, Ser404) epitopes via the activation of Akt [223,237]. Of great importance and relevance, was the finding that 8- workweeks of leptin treatment in CRND8 transgenic mice resulted in a ~2-fold decrease in tau phosphorylation at AT8 and PHF1 epitopes [221].Leptin fosters synaptogenesis and synaptic plasticity Several studies have shown that synaptic dysfunction and synaptic loss are the cardinal hallmarks of incipient AD [238-244]. Electron microscopy [238,241,245-248], immunohistochemical and biochemical studies [240,249-251] have demonstrated that synaptic loss in the neocortex and the hippocampus is an early episode in Alzheimer’s disease [252,253]. Synaptic loss is also the most important structural correlate of cognitive impairment in AD [250,254-260]. Synaptic dysfunction can be detected in patients diagnosed ith daft cognitive impairment (MCI), a designer which may or may not progress to AD and characterized by umteen as a prodromal state of AD [247,261]. Leptin plays an indispensable role in learning, memory, and maintenance of synaptic plasticity [262]. Leptin receptor mutant db/db mice and fa/fa  rats have deficits in spatial memory and piteous short term memory processing as assessed by the Morris water labyrinth [130] and T-maze footshock avoidance test paradigms [129]. In the CA1 region of the hippocampus, leptin exclusively enhances the NMDA receptor-mediated synaptic transmission [132].Leptin facilitates the trafficking of NMDA receptors to the plasma membrane and this may contribute to the effect of leptin on enhancing the NMDA receptor-mediated current [133]. This was also corroborated in a Xenopus oocyte seat system expressing recombinant NMDA receptors [132]. Leptin evokes the conversion of STP to LTP in acute hippocampal slices. Further delving into the molecular mechanism underlie this effect has implicated the PI3K/Akt and ERK signaling cascades at the nexus as the inhibitors of these signaling pathways mitigated this effect of leptin [132].Furthermore, in the CA1 region of the hippocampus, leptin also fosters the induction of a allegory form of LTD and this effect was attributed to NMDA receptor activation [263]. The study by Durakoglugil also examined the signal transduction cascades involved in the induction of this novel LTD by leptin and concluded that this effect was contingent on the PI3K signaling cascade, but independent of the ERK signaling pathway [263]. In addition to regulating synaptic lastingness by modulation of LTP and LTD, leptin also fosters synaptogenesis.The leptin lacking(predicate) ob/ob mice have decreased synapse density and exogenous leptin corrects this deficit in these mice [264,265]. Leptin also induces the expression of a multitude of pre- and postsynaptic proteins such as synapsin2A and synaptophysin in the hippocampus [266]. Leptin also has a profound effect on dendritic morphology. Leptin augments filopodial stabilization, fosters mobility and boosts their density, thus promoting synapse formation [267]. Interestingly, this effect of leptin on filopodial stability and density is continge nt on ERK signaling pathway and not on the PI3K signaling pathway [267].Leptin increases neuronal option and mitigates cell cobblers last There is growing consensus that leptin is a growth and survival factor in the CNS. Leptin increases the viability of SH-SY5Y cells and suppresses caspase-mediated cell end by down-regulation of caspase-10 and TRAIL and this effect is contingent on the ability of leptin to activate the JAK-STAT, PI3K-Akt, as well as ERK signaling pathways [268]. Leptin has been shown to exert neuroprotective properties in courteous MN9D rat dopaminergic cells against 6-OHDA.Leptin also averted the 6-OHDA-induced dopaminergic cell loss in the substantia nigra of mice when administered intracranially [269]. This pro-survival effect of leptin on dopaminergic neurons was attributed to the JAK2-dependent activation of the ERK signaling pathway resulting in increased levels of survival factors p-CREB and BDNF [269]. Our recent work has unequivocally demonstrated tha t leptin upregulates the expression of Insulin-like Growth Factor †1 (IGF-1), a known neurotrophic and survival factor in the brain [270].Leptin has also been shown to attenuate apoptotic cell death of cultured cortical neurons in an in vitro oxygen-glucose deprivation manakin of global ischemia [271]. Furthermore, the study by Zhang et al. , also cogently showed that intraperitoneal administration of leptin in mice reduce the infarct volume and significantly improved behavioral parameters in a optic cerebral artery occlusion (MCAO) put of global ischemia [271]. This effect of leptin was attributed to the activation of ERK signaling pathway as the general inhibitor of ERK signaling abolished this effect of leptin, both in vitro and in vivo [271].Another study employing hippocampal cultures has demonstrated that leptin inhibits neuronal cell loss in response to growth factor withdrawal and aerobic annoy by evoking JAK-STAT activation leading to compou nd expression Mn-SOD and Bcl-xL and stabilizing the mitochondrial membrane potential [135]. Leptin also mitigated neuronal loss in response to excitotoxic insult evoked by glutamate in hippocampal cultures by the aforementioned molecular mechanism [135]. Leptin also protected the hippocampal neurons from kainite-induced damage in response to excitotoxicity evoked seizures in a mice deterrent example of temporal lobe epilepsy [135].A recent study found that leptin also attenuates MPP+-induced cell death in neuronal cultures via the activation of STAT3 and inducing the expression of UCP-2 that culminates in the obviation of mitochondrial dysfunction by MPP+ [272]. Of particular interest is the finding that cultured cortical neurons secrete prodigious amounts of leptin in response to oxygen-glucose-serum deprivation that results in intensify expression of IL-1? and increased intransigence to apoptotic cell death [273].Moreover, neutralization of this endogenous leptin with an anti body resulted in increased susceptibility of these cultured cortical neurons to oxygen-glucose-serum deprivation †induced cell death [273]. The salutary effects of leptin on neuronal viability and function have also been corroborated by electrophysiological studies. One such study has cogently demonstrated that leptin combats the hypoxia-induced inhibition of spontaneously firing hippocampal neurons by activating the BK channels (large conductance Ca2+ activated K+ channels) [274].Leptin induces proliferation of neuronal progenitors †evokes neurogenesis As Alzheimer disease is typified with selective neuronal loss in the hippocampus and other regions of the brain, the debunking of the teaching that neurogenesis occurs exclusively prenatally and the revelation that neurogenesis persists in the adult mammalian brain has opened novel healthful avenues to combat the neuronal loss in AD. Chronic leptin treatment increases hippocampal neurogenesis in mice and induces pro liferation of adult hippocampal progenitor cultures [134].This effect of leptin on adult hippocampal neurogenesis is attributed to increased cell proliferation in the dentate gyrus and not enhanced cell differentiation or cell survival [134]. The study by Garza and colleagues unequivocally implicated the JAK2-STAT3 and PI3K-Akt signal transduction pathways in the leptin induced enhancement of hippocampal neurogenesis [134]. Furthermore, leptin rescues the attenuation in adult hippocampal neurogenesis in a mouse model of chronic unpredictable stress-evoked depression via the inhibition of GSK3? nd subsequent stabilization of ? -catenin [275]. Leptin has also been documented to evoke neurogenesis and angiogenesis in a mouse stroke model (Avraham et al. , 2011). Go to: ————————————————- Conclusion Here we have reviewed the modern-day knowledge on the protective role of the adipokine lept in and its signaling in Alzheimer’s disease. In conspectus, leptin impinges on all facets of Alzheimer’s disease pathophysiology (Figure 1). These attributes of leptin such as the decrease in A? production and increase of A? learance, reduction in tau hyperphosphorylation as well as increased synaptogenesis, increased memory, increased spatial learning, and increased neurogenesis catapult leptin treatment as a unique therapeutic intervention and an indispensable tool in the elucidation of biochemical mechanisms involved in the etiology of the sporadic form of Alzheimer’s disease. Marwarha , G. and Ghribi, O. Leptin signaling and Alzheimer’s disease Marwarha , G. and Ghribi, O. (2012) Leptin signaling and Alzheimer’s disease. American Journal of Neurodegenerative Disease, 1 (3), p. 45-265. Lifestyle nonpharmacological interventions can have a deep effect on cognitive aging. We have reviewed the available literature on the in effect(p)ness of anima l(prenominal) activity, ingenious stimulant, and socializing on the incidence of dementia and on the course of dementia itself. Even though personal activity appears to be sound in both delaying dementia onset and in the course of the disease, more research is needed before dexterous stimulation and socializing can be considered as treatments and prevention of the disease.Through our paper, we found that all three nonpharmacological treatments provide benefits to knowledge and overall social welfare in patients with age-related cognitive impairments. These interventions may be right in the management of dementia. Alzheimers disease (AD) is a neurodegenerative disorder with devastating consequences [1]. notwithstanding being the most common cause of dementia, affecting approximately 5. 4 one thousand thousand Americans [2] and almost 50% of people over the age 85 [3], no heal has yet been discovered.Efforts are also centering on the schooling of more effective strategie s to slow the progression of AD to increase the eccentric of life of those affected. Even a two-year delay in disease onset would reduce the prevalence of AD among Americans by two million people within fifty long time [4]. If an intervention that delayed the onset of AD by five years had been applied back in 1997, we would have seen a 50% reduction in AD incidence [4]. Research on strategies to slow the development and progression of AD is arguably more important now than ever before, since the number of people with AD is expected to or so triple over he attached forty years [4], and dementia is the most important contributor to disability in the elder [5]. Among others, three nonpharmacological interventions are especially relevant as they king positively influence cognition, general functioning, and overall quality of life. These three strategies are fleshly praxis,  apt stimulation, and social interaction. While there are studies that evaluate the role of individu al and multimodal interventions on AD, there is a lack of literature on the confederacy of all three.The purpose of this paper is to review key areas of the literature that focus on the effects of physical accomplishment, noetic stimulation, and socialization strategies on AD evolution, as they embodiedly play an important role in the management of Alzheimers disease. Physical employ encapsulates both aerobic good examples (e. g. , walking and cycle) and nonaerobic exercises (e. g. , strength and resistance training; flexibility and balance exercises). For intellectual stimulation, we examine studies that have evaluated the prognostic effects of either cognitive hobbies (e. g. reading, word puzzles, and card games) or cognitive training (e. g. , data processor training games/paradigms that target specific cognitive domains such as memory and attention). social interaction is defined as the mesh of an AD patient in group-related activities, such as mealtime conversations, su pport groups, or other forms of social engagement. The health benefits attributed to physical activity are numerous and well known. Exercise has been associated with a lower incidence in many chronic diseases, such as coronary heart disease [6], type 2 diabetes [7], obesity [8], cancer [9], fig up loss [10], and high blood pressure [11].We have reviewed the effects of physical exercise on cognition. Higher cardiorespiratory fittingness has been related to higher scores on tests of cognitive function [12]. A meta-analysis of randomise controlled trials examining the relationship between exercise and cognition showed modest improvements in attention, processing speed, executive director function, and memory among older adults in the treatment arms [13]. This is highly relevant for the older population, as it suggests that physical activity can serve as a prophylactic device measure against age-related cognitive decline [14].Several large longitudinal studies followed older adu lts without cognitive impairments at baseline and measured rate of happening dementia to clarify the relationship between physical activity and incident cognitive loss. A large prospective study by Podewils et al. identified an inverse relationship between physical activity and dementia risk [15]. Compared to no exercise, physical activity has been linked with reduced risks of developing cognitive impairment and dementia [16] with the risk for dementia being further reduced with increasing levels of physical activity.Larson and colleagues found that persons who exercised three or more times per week had a reduced risk of developing dementia compared to those who exercised less, and the reduction was more marked among those with the poorest physical function at baseline [17]. These results were corroborated by Buchman et al. who found that participants in the lowest percentiles of physical activity had more than twice the risk of developing dementia than those in the highest percent iles of physical activity [18].Furthermore, Lautenschlager et al. demonstrated that these results might be transferable to adults with mild cognitive impairment (MCI), and, thus, at high risk for dementia; participants who underwent exercise training showed modest improvements in cognition after six months [19]. Physical exercise has, therefore, been recommended as a impeding measure of mild cognitive impairment and dementia [20, 21]. There is much less research focusing on the effect of physical activity in AD patients.This may be due to the challenges of implementing an exercise regime while managing the behavioral and randy disturbances in AD patients, particularly in the later stages of the disease. However, the results in the available literature are promising. Early research involving AD patients in non randomised controlled trials showed significant cognitive improvements among participants who underwent cycling training and somatic and isotonic-relaxation exercises [22,  23]. Physical exercise may have beneficial effects in AD patients beyond cognition as well.A meta-analysis on 30 randomized controlled trials that employed exercise, behavioral and environmental manipulations in patients with cognitive impairment found exercise had positive effects on strength and cardiovascular fitness in addition to improvements in behavior and cognition [24â€26]. Further evidence supporting multifaceted positive effects of exercise on AD can be traced to recent randomized controlled trials of physical exercise regimes on AD patients (Table 1). Compared to controls, patients in the intervention programs showed better physical functioning (functional reach, walking, and mobility).After treatment, these patients also showed improved performance of activities of daily living (ADLs), and less cognitive decline and cognitive improvement in some cases. Physical exercise, therefore, appears to be beneficial for AD patients. While the majority of the studies did no t find any differences in depression, one study by Steinberg found increased depression and decreased quality of life in patients who underwent the exercise intervention [31]. Further research into the effect of physical exercise on mood and quality of life in AD patients is, therefore, unavoidable.When considering the role of exercise on AD, it is important to note that any positive results may be due to a placebo effect, even in randomized controlled trials. However, due to the varied nature of the outcome measures used in these studies, it is unlikely that every intervention group demonstrated significant gains over the controls due to a placebo effect alone. Furthermore, control group members never appeared to show any improvement and often showed higher rates of functional and cognitive decline.Enhanced neuroplasticity might be underlying the improvements seen. Colcombe and colleagues demonstrated that older adults without dementia who performed aerobic exercises had greater colorise and white matter volumes compared to adults who engaged in stretching and toning exercises [38]. Exercise has also been associated with functional connectivity between brain networks often affected by age, such as the omission mode, frontal parietal, and frontal executive networks, in older adults without dementia [39].While randomized controlled trials in AD patients examining the relationship between neuroplasticity and exercise are underway, correlational studies examining brain volumes and cardiorespiratory fitness have been done. In AD patients, cardiorespiratory fitness has been associated with brain volume. VO2 blooming, peak oxygen consumption, has been positively correlated with greater whole brain volume and white matter volume [40], notably in the inferior parietal lobule, hippocampal, and parahippocampal regions [41].Future results of randomized controlled trials will improve our knowledge in this field of research. Overall, physical activity offers promising o utcomes for cognition and physical health in the elderly population and AD patients. Engagement in intellectually stimulating activities has been linked with reduced risk of developing AD and intellectual stimulation has been widely explored as a nonpharmacological treatment option for dementia [42]. Among cognitively ormal older persons, randomized control trials employing intellectual training concluded that cognitive interventions produce protective and potentially long lasting positive effects in various cognitive domains as well as activities of daily living [43]. There is also evidence that frequent engagement in hobbies, including reading, puzzles, and games, for at least six hours per week reduces the risk of incident dementia [44]. The conceit of intellectual stimulation as a preventative measure for dementia in healthy older adults can be parallel to the notion of create a â€Å"compensatory mechanism” or â€Å"cognitive concur” [45â€48].Cognitive reser ve refers to the hypothesis that individual differences determine by inherent characteristics and external sources including intelligence, years of education, occupation, and intellectual activities, may provide neural protective support against dementia [45â€47]. It has been argued that these collective life experiences may contribute to building cognitive reserve and, thus, provide skills to treat for AD pathology [45â€47].In other words, a greater cognitive reserve might delay the appearance of dementia despite the presence of neuropathology, after which a rapid progression of cognitive decline may ensue once pathology is significant enough to result in AD diagnosis. Thus, AD patients with higher education and occupation accomplishments suffer more rapid decline in cognitive abilities when compared to AD patients with less education and occupational attainment following diagnosis [49]. Another study by Helzner and colleagues [50] investigated the relationship between pre morbid leisure activity and rate of cognitive decline in AD patients.Leisure activities were classified into four categories: intellectual, social, physical, and other. Higher-frequency participation in intellectual leisure activities prior to AD diagnosis was associated with delayed AD onset followed by faster cognitive decline. The study by Helzner and colleagues [50] provides evidence for the benefits of intellectual stimulation on slowing down AD development. to a fault reducing the risk of dementia, cognitive interventions later in life may affect functional decline in AD.Treiber and colleagues [51] explored the association between engaging in cognitively stimulating activities in late life and the rate of cognitive decline in incident AD. This study included a wide range of intellectual activities that required varying levels of cognitive demand, for example, completing puzzles, reading, ceremony television, listening to music, and cooking. The results suggested that higher- frequency participation in stimulating activities in early stages of dementia resulted in slower cognitive decline.However, as time progressed there was an overall decrease in participation in activities, which might polish the nature of AD in impairment of functional abilities. Intellectual stimulation can be divided into several categories including cognitive stimulation, cognitive t\r\n'