IMMUNO-ENDOCRINE DISTURBANCES IN ALZHEIMER DEMENTIA

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degrading enzyme, neprilysin) also catabolize insulin. (IDE), or are stimulated by somatostatin (neprilysin). Aging people and AD patients have low brain levels ...
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IMMUNO-ENDOCRINE DISTURBANCES IN ALZHEIMER DEMENTIA Liana Dehelean1, Elena D Stefan2, Pompilia Dehelean3, Ion Papavã4, Claudia C Vasilian5 Abstract: Introduction: Alzheimer Dementia (AD) is a primary dementia with a complex pathogeny. Genetic, endocrine, immunological and environmental factors contribute in various degrees to cognitive deterioration. Objectives: The present paper summarizes the complex interactions between genetic, endocrine and immunological factors that may be involved in the development of AD, or may aggravate it. Material and Method: The possible links between immunologic and endocrine factors associated with AD were collected from data published in psychiatry, immunology and endocrinology journals. The research focused on hormones that are involved in cell metabolism and growth (insulin and somatostatin) and in cell metabolism and cognitive functioning (thyroid hormones). Results: Neuronal activity is influenced by neurotransmitters, hormones and cytokines (interleukins) that use secondary messengers to influence enzymes (GSK-3â) and gene transcription factors. Through protein phosphorylation, GSK-3â controls synaptic transmission (voltage-dependent calcium channels), synaptic structure (â catenin), intra-axonal transmission (protein tau), and neuronal metabolism. There are complex reciprocal relationships between neurotransmitters, hormones and cytokines. Amyloid â stimulates the immune response. Enzymes that reduce amyloid â42 levels (IDE / insulindegrading enzyme, neprilysin) also catabolize insulin (IDE), or are stimulated by somatostatin (neprilysin). Aging people and AD patients have low brain levels of somatostatin, a hormone that regulates insulin and TSH secretion. Conclusion: AD may be independently associated with overt autoimmune or with subclinical hypothyroidism, as well as with insulin and non insulin dependent diabetes mellitus. These conditions may enhance the cognitive deterioration and therefore, it is important to be identified and corrected. Also, a possible target in the treatment of diabetes and AD may be the enzyme GSK-3â, using GSK-3 inhibitors. Keywords: Alzheimer dementia, hypopthyroidism, diabetes mellitus, autoimmunity.

Rezumat: Introducere: Demenþa Alzheimer (DA) este o demenþa primarã cu patogenie complexã. Factori genetici, endocrini, imunologici ºi ambientali contribuie în grade variate la deteriorarea cognitivã, motiv pentru care, în evoluþia bolii trebuie luaþi în considerare. Obiective: Lucrarea de faþã îºi propune sã investigheze interacþiunile complexe dintre factorii genetici, endocrini ºi imunologici care ar putea fi implicaþi în patogenia DA sau pot accentua evoluþia acesteia. Material ºi metodã: Au fost cãutate relaþiile dintre factorii imunologici ºi endocrini asociaþi cu DA analizând articolele publicate în reviste de psihiatrie, imunologie, endocrinologie. Cercetarea a fost orientatã pe hormonii implicaþi în creºtere ºi metabolism (insulina, somatostatina), sau în metabolism ºi cogniþie (hormonii tiroidieni). Rezultate: Activitatea neuronalã este influenþatã de neuromediatori, hormoni ºi citokine (interleukine) ce acþioneazã asupra unor sisteme de mesageri secunzi influenþând enzime (GSK-3â) ºi factori activatori ai transcripþiei genetice. Prin fosforilare proteicã, GSK-3â controleazã transmisia sinapticã (canalele de calciu voltaj-dependente), structura sinapsei (â catenine), transmisia axonalã (proteina tau) ºi metabolismul neuronal. Între neuromediatori, hormoni ºi citokine existã relaþii reciproce complexe. Amiloidul â stimuleazã rãspunsul imun. Enzimele care reduc nivelele de amiloid â42 (IDE, neprilysina) catabolizeazã insulina (IDE), sau sunt stimulate de somatostatinã (neprilysina). Vârstnicii ºi pacienþii cu DA au nivele reduse de somatostatinã, hormon care la rândul sãu, controleazã secreþia de insulinã ºi de TSH. Concluzie: În unele cazuri, DA se poate asocia independent cu tiroidita autoimunã sau cu hipotiroidismul subclinic, respectiv cu diabetul zaharat insulino- ºi non insulino-dependent. Aceste stãri comorbide pot agrava deteriorarea cognitivã ºi din acest motiv, ele trebuie identificate ºi tratate corespunzãtor. De asemenea, o posibilã þintã terapeuticã în diabetul zaharat ºi DA, ar putea fi chiar GSK-3â, prin utilizarea inhibitorilor enzimei GSK-3. Cuvinte cheie: demenþa Alzheimer, hipotiroidism, diabet zaharat, autoimunitate.

1 Lecturer in Psychiatry at Psychiatric Department of “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania. Contact e-mail: [email protected], tel/fax: +40 256 294134 2 Resident in Psychiatry at “Eduard Pamfil” Psychiatric Clinic, Timisoara, Romania 3 Professor of Psychiatry at Psychiatric Department of “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania 4 Assistant lecturer in Psychiatry at Psychiatric Department of “Victor Babes”University of Medicine and Pharmacy, Timisoara, Romania 5 Resident in Psychiatry at “Eduard Pamfil” Psychiatric Clinic, Timisoara, Romania Received August 05, 2011, Revised October 03, 2011, Accepted November 22, 2011.

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Liana Dehelean, Elena D Stefan, Pompilia Dehelean, Ion Papavã, Claudia C Vasilian : Immuno-endocrine Disturbances In Alzheimer Dementia INTRODUCTION Alzheimer Dementia (AD) is a primary dementia with a complex pathogeny, where genetic, endocrine, immunological and environmental factors contribute in various degrees to cognitive deterioration. The accumulating amyloid â stimulates the brain immune response. Genetic factors may increase the individual's vulnerability to autoimmune disorders, as well. Acting on central nervous and endocrine systems, autoimmune disorders aggravate the cognitive deterioration induced by AD. GSK-â (glycogen synthase kinase 3â) is an enzyme involved in glucose and protein metabolism. In brain, GSK-3â controls inter-neuronal transmission (synaptic transmission, synaptic structure) as well as intra-neuronal transmission (microtubule dynamics). Acting on proapoptotic proteins (Bax) and on cyclin D1 (1) GSK-3â regulates neuronal survival. Through presenilin 1 phosphorylation, GSK-3â stimulates amiloyd â synthesis, while through hyperphosphorylation of tau protein, GSK3â stimulates the production of neurofibrillary tangles. Its activity is regulated by several neurotransmitters (dopamine), hormones (insulin, somatostatin, thyroid hormones) and cytokines (IFNã). While mediating neurotransmitter and hormonal intracellular responses, GSK-3â stimulates also the production of pro-inflamatory cytokines (IL6 and IL12). As a consequence, GSK-3â is a metabolic key enzyme where the central nervous system, the endocrine system and the immune system interconnect (fig 1).

Figure 1: synthesis: Autoimmunity plays an important role, among other pathogenic factors, in the development of hypothyroidism and diabetes mellitus. On the other hand, autoimmunity may alter neurogenesis and induce neurodegeneration. GSK-3â activity is influenced by autoimmune factors, neurotransmitters and hormones. Beside its metabolic roles, GSK-3â controls the synaptic transmission and the intra-axonal transport, thus influencing cognition. OBJECTIVE The objective of the present paper is to summarize the complex interactions between genetic, endocrine and immunological factors that are involved in the development of Alzheimer dementia (AD) or in its 174

aggravation. The genetic factors may induce familial and sporadic forms of AD. Endocrine factors influence cognition by activating enzymes involved in amyloid â degradation, or by regulating the synthesis, metabolism and activity of neurotransmitters. Immunological factors have reciprocal links with neurotransmitters and hormones. METHOD The possible interconnections between immunologic and endocrine factors associated with AD were collected from data published in psychiatry, immunology and endocrinology journals. The research focused on hormones that are involved in cell metabolism and growth (insulin and somatostatin) and in cell metabolism and cognition (thyroid hormones). Immune factors are involved in insulin dependent diabetes mellitus (IDDM, type 1 diabetes mellitus), non insulin dependent diabetes mellitus (type 2 diabetes mellitus) and hypothyroidism. Knowing the fact that AD is more frequent in women, the relationship between estrogen hormones, cognition and AD was also investigated. RESULTS The genes intervene in AD pathogeny in different degrees producing genetic and sporadic forms of AD. The genetic (familial) early onset forms of AD are generated by single - gene mutations on certain chromosomes such as: chromosome 21 (containing genes for amyloid precursor protein), chromosome 14 (containing genes for presenilin 1) and chromosome 1 (containing genes for presenilin 2). Presenilins 1 and 2 are components of ã secretase. This membrane enzyme, acting with â secretase, produces amyloid â from amyloid precursor protein (APP). Amyloid â, in its dimeric form, is soluble and regulates the cholesterol content of the synaptic membrane. If amyloid â is excessively produced or insufficiently eliminated by apolipoproteins E (APO E), it polymerizes forming insoluble tetramers and hexamers. Chromosome 21 is also involved in the pathogeny of the Langdon-Down syndrome (trisomy 21) affecting neurogenesis and inducing mental retardation. The patients with Down syndrome that survive till maturity have an increased risk to develop AD. Sporadic, late onset forms of AD are the result of cumulative interactions between environmental factors and gene variants encoding APO E. The å4 alleles of the APO E genes are associated with an increased risk for developing AD (low affinity of APO E å4 for amyloid â) and cardio-vascular diseases (increased plasmatic cholesterol). The levels of amiloyd â depend on several degradative enzymes such as: NEP (neprilysin), IDE (insulindegrading enzyme, insulysin), ECE-1, ECE-2 (endothelin converting enzyme 1 and 2) and probably plasmin (2). The expression of neprilysin is regulated by several factors such as: aging (2) hormones: estrogens (2) and somatostatin (3) exercise (2) environmental enrichment (2) Insulin is a polypeptide synthesized by the â cells of the

Romanian Journal of Psychiatry, vol. XIII, No.4, 2011 pancreatic Langerhans islets. It is an important hormone that regulates carbohydrate, lipid, and protein metabolism. Because IDE is involved in the catabolism of both insulin and amyloid â, variations of IDE encoding gene may increase the risk for both AD and type 2 diabetes mellitus. Low levels of brain IDE result in reduced amyloid â catabolism and its accumulation, while reduced insulin degradation results in hyperinsulinemia. Clinical studies revealed an increased risk to develop AD in patients with type 2 diabetes mellitus and hyperinsulinemia (4). The hippocampal expression of IDE is reduced in APO E å4 positive patients with AD (2). In the absence of APO E å4 allele, the risk of late onset AD is increased by IDE gene variations (4). Insulin influences the phosphorylation of tau protein (5). By acting on its tyrosinkinase receptors, insulin activates PI3K which initiates an enzymatic cascade resulting in the inhibition of GSK-3â (fig. 2). This enzyme controls: -neuronal metabolism -synaptic structure (influencing â catenin) -synaptic transmission (influencing voltage-dependent calcium channels) -intra-axonal transport (influencing tau protein)

Figure 2. GSK-3â is a key metabolic enzyme influencing protein and glucose metabolism. It also has pro-apoptotic activity and inhibitory effects on IL-10 synthesis. Neurotransmitters influence GSK-3â activity through secondary messengers that activate protein kinases A and C. Insuline stimulates through protein kinase B (PKB), the phosphorylated form of GSK-3â which is inactive. Somatostatin stimulates protein phosphatases, which inhibit protein kinases and stimulate the active form of GSK-3â The intra-axonal transport is made possible by microtubule polymerization and depolymerization. Microtubule associated proteins, such as tau protein, stabilize the microtubules. Through tau protein hyperphosphorylation, GSK-3â impairs its interaction with the microtubules. As a consequence, the microtubules network will collapse forming the neurofibrillary tangles, one of the histological markers of AD. Through GSK-3â inhibition, insulin will not only influence the neuronal metabolism, but also the intraaxonal and inter-neuronal (synaptic) transmission. The hippocampal formation (CA1, CA3, dentate gyrus), which is first region affected by the pathologic processes

in AD, has insulin receptors. Insulin is essential for the transport of glucose into brain cells. Glucose is catabolised through aerobic glycolysis into acetyl CoA, an enzyme from which acetylcholine is synthesized (6). In addition, insulin activates the muscarinic acetylcholine receptors and modulates glutamate and GABA receptors (7). Insulin is important also in the cholesterol metabolism. Cholesterol and triglycerides are transported in plasma through the aid of lipoproteins. Among these, chylomicrons transport triglycerides from intestine to peripheral tissues, while HDL (high-density lipoprotein) transports free cholesterol from peripheral tissues to liver. Being involved in the reverse cholesterol transport, HDL has anti-atherogenic and cardioprotective properties. VLDL (very low density lipoprotein) and LDL (low density lipoprotein) transport triglycerides and cholesterol (respectively) from liver to peripheral tissues. HDL has two major subfractions HDL3 and HDL2. Plasma LCAT (lecithin - cholesterol acyltransferase) converts free cholesterol into esterified cholesterol (cholesteryl ester) stimulating the transformation of pre â – HDL (discoidal HDL, a cholesterol acceptor) into HDL3 and further into HDL2. Plasma CETP (cholesteryl ester transfer protein) redistributes esterified cholesterol from HDL to APO B lipoproteins in exchange for triglycerides (8). APO B lipoproteins (VLDL remnants / IDLintermediate density lipoproteins and LDL) are removed from circulation by the liver through LRP / LDL receptor related protein. HDL removes cholesterol binding hepatic SRB-1R / scavenger receptor B-1 (9), (10). Acting on hepatic lipase, insulin favors the conversion of HDL2 to HDL3, while in the peripheral circulation, insulin induces HDL2 formation acting on lipoprotein lipase (11). Cholesterol is an important component of the synaptic membranes: - in the membrane of the synaptic vesicle, cholesterol stabilizes the synaptobrevin-synaptophysin complex; - in the presynaptic neuronal membranes, cholesterol is a component of the active parts of these membranes, called lipid rafts (where the synaptic vesicles attaches to the presynaptic membrane). As a consequence, decreased cholesterol content in neuronal membranes will impair synaptic transmission, and thus, cognition. Yet, excessive cholesterol in neuronal membranes is harmful because it binds to APP near to the alpha secretase cleavage site, blocking its activity (7). This results in the enhancing of the gamma secretase and beta secretase activity, with amyloid â synthesis (12). In turn, amyloid â 40 will diminish the synthesis of cholesterol by inhibiting HMGCoA (3-hydroxy-3methyl-glutaryl-CoA) reductase (13). HDL containing LCAT extracts cholesterol from the neuronal membranes. By lowering excessive cholesterol content from the neuronal membranes, HDL may decrease amyloid â synthesis (14). Low LCAT activity was found in patients with AD or with Down syndrome, and there is a risk for patients with Down syndrome to develop AD. Low levels of HDL are considered an important risk factor for developing coronary artery disease and AD. Nevertheless, raising HDL levels was not associated with memory improvements (14). Plasma cholesterol does not penetrate the blood-brain barrier, but its metabolite 24 S hydroxycholesterol does, 175

Liana Dehelean, Elena D Stefan, Pompilia Dehelean, Ion Papavã, Claudia C Vasilian : Immuno-endocrine Disturbances In Alzheimer Dementia reflecting the rate of brain cholesterol metabolism. Cholesterol is synthesized in brain by astrocytes and transported to neurons with the aid of HDL. Brain HDL is generated from APO E and APO J lipoproteins synthesized by astrocytes and microglia (15). In neurons, cholesterol is catabolised into 24 S hydroxycholesterol, which has an inhibitory effect on beta secretase. In patients with AD, high levels of 24 S hydroxycholesterol were found at the onset of the illness, while in the advanced stages the levels were low. It is possible that the high levels of 24 S hydroxycholesterol found at the onset of AD may reflect a compensatory mechanism aimed to reduce amyloid â production. It is important to emphasize that for good cognitive functioning cholesterol and gangliosides should be correctly distributed among cell compartments: neuronal membranes, lysosomes, mitochondria, endoplasmic reticulum. Accumulation of cholesterol in lysosomes (as it happens in Niemann – Pick disease type C) is followed by mental retardation and cognitive decline. Somatostatin, also known as SRIF/somatotropin releaseinhibiting factor (fig. 3) is a neuropeptide which modulates endocrine, growth factor, neurotransmitter, and cytokine secretions. The wide actions of somatostatin can be summarized as follows: - hormone release inhibition: growth hormone (GH), glucagon, insulin, prolactin, thyrotropin (TSH / thyroidstimulating hormone), corticoropin, cortisol, epinephrine - neurotransmitter release modulation: acetylcholine, dopamine, serotonin, norepinephrine - growth factors release inhibition: IGF1, EGF, PDGF - cytokine secretion inhibition: IL6, IFN-ã (16)

Figure 3. Somatostatin acts on receptors coupled with G proteins. Stimulating the Giá subunit of receptor coupled G proteins, somatostatin inhibits the adenylate cyclase, and consequently, protein kinase A. Stimulating the Gqá subunit of receptor coupled G proteins, somatostatin activates phospholipase C and consequently protein kinase C. Acting on G12/13 subunits of receptor coupled G proteins, somatostatin influences Rho protein kinases. Somatostatin also stimulates the protein phosphatases, enzymes that inactivate the protein kinases. Somatostatin receptors (SSTRs) are coupled with adenylate cyclase, ionic channels (calcium, potassium), serine/threonine phosphatases, and tyrosine phosphatases (17). By inhibiting adenylate cyclase and stimulating 176

potassium efflux, somatostatin exerts its inhibitory effects on hormones secretion. By stimulating phosphatases, somatostatin inhibits cell proliferation (SSTR 1, 2, 4, 5) and stimulates (SSTR 3) apoptosis (18), (19), (16). Its own release is modulated by neurotransmitters (20) and hormones. GH and thyroid hormones enhance somatostatin secretion from the hypothalamus (16). Glucocorticoids exert a dose-dependent biphasic effect on somatostatin secretion, with low doses being stimulatory and high doses inhibitory. Insulin stimulates hypothalamic somatostatin release but has an inhibitory effect on the release of islet and gut somatostatin (16). The inflammatory cytokines IL-1, TNF-á, and IL-6 stimulate somatostatin secretion and mRNA levels from cultured rat brain cells. Somatostatin receptors are found in structures involved in cognitive processing: hippocampus (CA1), dentate gyrus, subiculum, entorhinal and frontal cortex (21). Studies in rats revealed that activation of somatostatin receptor 5 facilitates the function of glutamate NMDA receptors involved in long-term potentiation (22). Somatostatin enhances endogenous acetylcholine release in the rat hippocampus (23). The administration of octreotide (a synthetic analogue of somatostatin) in rats increases the cholinergic activity in hippocampus (21). Somatostatin is also colocalized with GABA in interneurons (22). Somatostatin may be involved in cognition in at least two ways: increasing the activity of neprilysin which inhibits amyloid â42 synthesis (3), and modulating cholinergic neurotransmission. Somatostatin expression in brain declines with age (3), (17). Its receptors are reduced in the brain of AD patients: a 50% reduction in the frontal (Brodmann areas 6, 9, 10) and temporal (Brodmann area 21) cortexes, while in the hippocampus, the reduction was about 40% (24). Another study found that in the brain of AD patients there is a reduction of SSTR 2, 4, 5, an increase in SSTR 3, no changes in SSTR 1, and reduced levels of somatostatin in the cortex and the cerebrospinal fluid (25). Aging-induced downregulation of somatostatin expression may trigger Aâ accumulation leading to lateonset sporadic AD (3). In patients with AD there is a reduced CNS expression of genes encoding insulin, IGFs (insulin-like growth factors) I and II, as well as a reduced expression of insulin and IGF-I receptors (26). A study performed on patients with AD, showed that the administration of intranasal insulin improves verbal memory in AD without the APO E å4 allele (27). AD patients without an APO E å4 allele had lower insulin levels than patients presenting APO E å4 allele and despite similar insulin infusion rates and body mass, women with AD have lower insulin levels than men with AD (21). In another study, hyperglycemia associated with hyperinsulinemia (dextrose plus insulin) as well as administration of somatostatin analogue - octreotide alone were associated with memory improvement (21). Hyperglycemia with fasting insulin (dextrose plus octreotide) was not associated with memory improvement. In the same study, hyperinsulinemia induced high levels of cortisol in AD patients, while somatostatin analogue - octreotide administration was associated with reduced cortisol, corticotrophin and epinephrine levels in AD patients and in healthy subjects. Both type 1 and type 2 diabetes mellitus have immune

Romanian Journal of Psychiatry, vol. XIII, No.4, 2011 status alterations among risk factors. Acute phase reactants (C-reactive protein), interleukins (IL-6) and adipokines (adiponectin) are factors involved in the pathogenesis of type 2 diabetes mellitus, acting independently of age, sex, glycemia, family history of diabetes, physical activity, smoking, and baseline atherosclerosis (28). In addition, drugs with antiinflammatory properties such as aspirin and statins have beneficial effects on type 2 diabetes mellitus. Statins inhibit the production of cholesterol, cytokines (IL-1â, TNF-á), and the action of IL-6 at the liver level (28). In insulin-dependent diabetes mellitus (IDDM), glutamic acid decarboxylase was identified as the major target for autoantibodies directed against the pancreatic islet â-cell (29). This antigen is also found in other autoimmune diseases that form together with IDDM the type 2 autoimmune polyglandular syndrome also known as Schimidt's syndrome. This syndrome encompasses: Addison's disease, IDDM and autoimmune diseases such as Hashimoto's thyroiditis, primary myxedema, symptomless autoimmune thyroiditis, Graves' disease, isolated ophthalmopathy (30). Thyroid hormones are involved in neurogenesis and brain metabolism influencing cognitive functions. Prenatal hypothyroidism inhibits axonal elongation and dendritic ramification affecting synaptogenesis. Postnanal hypothyroidism induces in rats a lower rate of differentiation, a lower number and lower dimensions of hippocampal granular neurons (31). A community-based study found an association between sublinical hypothyroidism and dementia (32). Subclinical hypothyroidism (elevated TSH in the presence of normal thyroxin concentrations) is more prevalent than overt (clinical) hypothyroidism especially in elderly and particularly in women (33). Its prevalence is 5-10% in general population and the progression risk to overt hypothyroidism is increased in the presence of antithyroid antibodies (34). A study conducted in patients with Down syndrome found that they present low levels of thyroid hormones, increased levels of TSH and increased levels of antithyroglobulin and antimicrosomal antibodies compared with normal subjects. In addition, patients with Down syndrome and AD had lower titers of T3 associated with higher levels of antithyroglobulin and antimicrosomal antibodies, compared with normal subjects (35). The fact that AD is more prevalent in women raised the question whether estrogen hormones are involved in the pathogenesis of dementia. Estrogen hormones may influence cognitive functioning by stimulating the activity of choline acetyltransferase, which is involved in acetylcholine synthesis. In addition, estrogen hormones stimulate alpha secretase, the enzyme that produces a soluble form of amyloid. Nevertheless, clinical studies showed that substitutive treatment with sexual hormones in women after menopause failed to improve cognition and increased the risk of dementia, cancer and cardiovascular diseases (36). CONCLUSION The body hormonal status influences cognition through neuronal metabolism and transmission, or through vascular complications of high plasma cholesterol. The immune factors may alter cognition directly, or acting on the immune-neuro-endocrine connections.

AD may be associated with overt autoimmune hypothyroidism or IDDM. A genetic variation involving the IDE gene increases the risk for both AD and type 2 diabetes mellitus. New data involve the immune factors in the pathogenesis of type 2 diabetes mellitus. Subclinical hypothyroidism may progress to overt hypothyroidism, in the presence of antithyroid antibodies. Because diabetes mellitus and hypothyroidism aggravate the cognitive deterioration induced by AD, recognizing and treating these co-morbidities may help prognosis. Another possible target for diabetes and AD may be the GSK-3 enzyme, using specific GSK-3 inhibitors (37). LIST OF ABBREVIATIONS: Aâ - Amyloid beta Acetyl CoA - Acetyl coenzyme A AD-Alzheimer Dementia APO E - Apolipoprotein E APP - Amyloid precursor protein Bax - Bcl-2 associated X protein, group-1 tumor necrosis factor family mediated cell death factor CA1, CA3 - Cornu Ammonis area 1, Cornu Ammonis area 3 CETP - Cholesteryl ester transfer protein CNS - Central nervous system ECE-1, ECE-2 - Endothelin converting enzyme 1, 2 EGF - Epidermal growth factor GABA – Gamma aminobutyric acid GH - Growth hormone GSK-3â - Glycogen synthase kinase-3 beta HDL - High-density lipoprotein HMGCoA - 3-hydroxy-3-methyl-glutaryl-CoA IDE - Insulin-degrading enzyme IDDM - Insulin dependent diabetes mellitus, type 1 diabetes mellitus IDL- Intermediate density lipoproteins IFNã - Interferon-gamma IGF1 - Insulin-like growth factor 1 IL-1 - Interleukin 1 IL-6 - Interleukin 6 IL-10 - Interleukin 10 LCAT - Lecithin - cholesterol acyltransferase LDL - Low density lipoprotein LRP - LDL receptor related protein mRNA - Messenger ribonucleic acid NEP - Neprilysin NMDA - N-Methyl-D-aspartic acid PDGF - Platelet-derived growth factor PI3K - Phosphoinositide 3-kinase PKB - Protein kinase B SRB-1R - Scavenger receptor B-1 SRIF - Somatotropin release-inhibiting factor SSTRs - Somatostatin receptors T3 - Triiodothyronine TSH -Thyroid-stimulating hormone VLDL - Very low density lipoprotein REFERENCES 1. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen syntase kinase-3â regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12(22):3499-3511. 2. Eckman EA, Eckman CB. Aâ-degrading enzymes: modulators of Alzheimer's disease pathogenesis and targets for therapeutic intervention. Biochemical Society Transactions 2005; 33(5):1101-1105.

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