Kísérleti Orvostudományi Kutatóintézet. Demencia/Alzheimer. Barna István KOKI

Átírás

1 Kísérleti Orvostudományi Kutatóintézet Demencia/Alzheimer Barna István KOKI

2 Diagnostic and Statistical Manual of Mental Disorders (DSM-IV: Dementia, Delirium, Amnesia) Jelentős kognitív hanyatlás Dementia is a general term for a decline in mental ability severe enough to interfere with daily life. MÉRÉSE: Mini Mental State Examination (MMSE) Értékelés Normál: pont Enyhe demencia: pont Közepes fokú demencia: pont Súlyos fokú demencia: < 10 pont

3 REVERZIBILIS DEMENCIÁK Drog Emocionális betegségek (depresszió, szorongás) Metabolikus betegségek (pl. cukorbaj) Érzékszervi fogyatékosságok Neurológiai betegségek Trauma, tumor Infekció Alkoholmegvonás anyagok/2014_osz/9_demencia_hi_update_bzs_2014.pdf

4 DSM-IV: Dementia 9. Dementia due to... [indicate other general medical condition] (Diagnostic and Statistical Manual of Mental Disorders) 1. Dementia of the Alzheimer s Type Without behavioral disturbance With behavioral disturbance 2. Vascular dementia 3. Dementia due to HIV disease 4. Dementia due to head trauma 5. Dementia due to Parkinson's disease 6. Dementia due to Huntington's disease 7. Dementia due to Pick s disease 8. Dementia due to Creutzfeldt- Jakob Disease

5 Epidemiology and risk factors of dementia De! 65-év alatt a demenciák előfordulása statisztikailag ill. társadalmi-lag alig jelentős

6 Demográfia

7 *** DSM Dementia Dementia of the Alzheimer s Type, with early onset Without behavioral disturbance With behavioral disturbance Dementia of the Alzheimer s Type, with late onset Without behavioral disturbance With behavioral disturbance Vascular dementia Uncomplicated With delirium With delusions With depressed mood Dementia due to HIV disease Without behavioral disturbance With behavioral disturbance Dementia due to head trauma Without behavioral disturbance With behavioral disturbance Dementia due to Parkinson's disease Without behavioral disturbance With behavioral disturbance Dementia due to Huntington's disease Without behavioral disturbance With behavioral disturbance Dementia due to Pick s disease Without behavioral disturbance With behavioral disturbance Dementia due to Creutzfeldt-Jakob Disease Without behavioral disturbance With behavioral disturbance Dementia due to... [indicate other general medical condition] Without behavioral disturbance With behavioral disturbance Dementia NOS

8 *** Részösszefoglalás Demencia: jelentős kognitív hanyatlás, többnyire visszafordíthatatlan, általában lassan progrediál, szövettani háttere legtöbbször: neurodegeneráció = neuron pusztulás. Tünettana az agyszöveti kárododás anatómiai lokalizációjától függ. Általában jelentős agytérfogat-csökkenéssel jár. A mentális deficit arányos lehet az agyszöveti veszteséggel ill. az agyi metabolikus ráta csökkenésével (energia- és oxigénellátás). A modern képalkotó eljárások az egyes demenciákra jellemző makro-anatómiai elváltozások mellett bizonyos kémiai elváltozások kimutatására, avagy a vérellátás minőségére nezve is jelentős információt adnak. Nagyobb populaciót vizsgálva a különböző demenciák kölönböző gyakorisági, életkorbeli és nemi megoszlást mutatnak. A különböző demenciák kisebb részben genetikai (familiális) okokra vezethetők vissza, általában azonban nem genetikus meghatározottságúak.

9 Alzheimer betegség

10 The Impact of Alzheimer's Disease on the Chinese Economy Alzheimer betegség költségvonzata Kanadában $15 billion $37 billion $75 billion $153 billion Magyarországon ( Skultéty László) Alzheimeresként Kvázi Alzheimeresként Összesen BNO F00, G30 F07 Betegszám aktív ágyon Esetszám aktív ágyon Ápolási nap Költség (HBCS alapon) 63 millió Ft 240 millió Ft 303 millió Ft 2004-es ár 5000 beteg beteg Első vizsgálat millió Ft 581 millió Ft Kontroll évi 1X millió Ft 78 millió Ft Házi szakápolás 2850 Ft/alkalom (10) 170 millió Ft

11 FŐBB TÜNETEK -memória veszteség -megoldóképesség hanyatlása -(tervezés, szervezés, okokozat..) -tájékozodási zavarok - öngondoskodás hanyatlása - elmagányosodás - érzelmi labilitás Súlyos Alzheimer: Aphasia: - beszéd készség/megértés Apraxia: mozgás zavarok Agnosia: személyfelismerési problémák

12 *** Aloysius "Alois" Alzheimer , MD 1889, Frankfurt am Main: the Städtische Anstalt für Irre und Epileptische 1889, Franz Nissl 1901, Auguste Deter, , Auguste Deter meghal delerium and frenzied jealousy cognitive and language deficits, auditory hallucinations, paranoia aggressive behavior unable to care for herself we would today call presenile dementia. thinning of the cerebral cortex senile plaque ( miliary foci ) tangles ( dense bundles of fibers ) in the cerebral cortex. 1910, Kraepelin, Ein Lehrbuch für Studierende und Ärzte. II. Band, Klinische Psychiatrie.

13 The gold standard for Alzheimer's diagnosis thinning of the cerebral cortex senile plaque ( miliary foci ) neurofibrillary tangles ( dense bundles of fibers ) in the cerebral cortex.

14 Makromorfológiai elváltozások thinning of the cerebral cortex vascular

15 Makromorfológiai elváltozások

16 *** Részösszefoglalás A különböző demenciák általában (bár nem minden esetben) jelentős agyi idegsejtpusztulás következményei. Az idegsejtpusztulás mértéke, anatómiai eloszlása és kiváltó oka sokféle lehet. Az időskori demenciák során bekövetkező makroanatómiai elváltozások egyik jól mérhető mutatója az agykamrák megnagyobbodása. Alzheimer betegségben elsősorban az agykéreg, az amygdala és a hippocampus károsodik.

17 Szövettani elváltozások, senile plaque megértése Egy kis fehérjekémia

18 Senile plaque megértése: amiloidózis

19 Amiloidózis Betegség Fehérje aggregátum Lugol 1. Alzheimer-kór ß-amiloid (plakkok) 2. Parkinson-kór a-synuclein /ubiquitin 3. Lewy-testes demencia a-synuclein 4. Huntington-kór poli-glutamin / ubiquitin 5. Prion-betegség prion protein (Creutzfeld-Jacob kór)

20 Mol Cell Neurosci August ; 51(1-2):

21 Amyloid Precursor Protein Is Trafficked and Secreted via Synaptic Vesicles Immunolabeling of fixed hippocampal neurons for APP synaptotagmin 1

22 APP az egészséges működésű szinapszisban amiloid prekurzor protein

23 Senile plaque ( miliary foci ) = Béta-amiloid plakk (Aβ: amyloid-β, Aβ1-42) Aβ1-42 : H2N - Asp - Ala - Glu - Phe - Arg - His - Asp - Ser - Gly - Tyr - Glu - Val - His - His - Gln - Lys - Leu - Val - Phe - Phe - Ala - Glu - Asp - Val - Gly - Ser - Asn - Lys - Gly - Ala - Ile - Ile - Gly - Leu - Met - Val - Gly - Gly - Val - Val - Ile - Ala - COOH

24 Direct Binding of Cholesterol to the Amyloid Precursor Protein: An Important Interaction in Lipid-Alzheimer s Disease Relationships? Lipid raft Secondary structure and membrane topology of C99 and location of the focal point for its recognition and binding of cholesterol (redhighlighted sites),

25 Pozitron emissziós tomográfia (PET) 18F Fluorodeoxyglucose Pittsburgh compound B (PiB) is a radioactive analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue.

26 Levels of beta-secretase (BACE1) in Cerebrospinal Fluid as a Predictor of Risk in Mild Cognitive Impairment

27 This study confirms that APP protein is a functional player in synaptic structure-functional plasticity... in... neurochemical pathways. Perspektíva: Metabolome in progression to Alzheimer's disease

28 Metabolome vizsgálatok Using direct infusion mass spectrometry for serum metabolomics in Alzheimer s disease November 2014, Volume 406, Issue 28, pp pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F %252Fs *~hmac=738c1a5f5ee087cb08daa58729d768c407817b0161b6e133d5790fbace8c1f14 Metabolomic analysis of serum was performed by extracting samples in a two-stage sequential procedure, followed by analysis with high-resolution tandem mass spectrometry, using electrospray (ESI) source in both positive and negative ionization modes.

29 Δ m mass error, FC fold change, CV coefficient of variation in QCs, VIP variable importance in the projection, AUC area under the curve, P Positive mode, N negative mode, POL polar extract, LIP lipophilic extract, LPC lyso-phosphocholine, PC phosphocholine, PPC choline-plasmalogen, PPE ethanolamine-plasmalogen

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31 DOI: awu255 First published online: 10 September (2016)

32 Soluble Aβ oligomers bind with high affinity to synapses on a subset of hippocampal and cortical neurons, indicative of specific binding to discrete cell surface receptors. In rodent hippocampal slice preparations, synaptic binding leads to rapid inhibition of and injection of various soluble Aβ oligomer preparations directly into the rodent brain leads to reversible impairment of cognitive function [31, 33, 110].

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34 *** DSM-IV criteria for the diagnosis of Dementia of the Alzheimer's Type A. The development of multiple cognitive deficits manifested by both: 1.Memory impairment (impaired ability to learn new information or to recall previously learned information) 2.One or more of the following cognitive disturbances: (a) aphasia (language disturbance) (b) apraxia (impaired ability to carry out motor activities depite intact motor function) (c) agnosia (failure to recognize or identify objects despite intact sensory function) (d) disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting) B. The cognitive deficits in criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. C. The course is characterized by gradual onset and continuing cognitive decline. D. The cognitive deficits in Criteria A1 and A2 are not due to any of the following: (1) other central nervous system conditions that cause progressive deficits in memory and cognition (e.g., cerebrovascular disease, Parkinson's disease, Huntington's disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor) (2) systemic conditions that are known to cause dementia (e.g., hypothyroidism, vitamin B or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection) (3) substance-induced conditions E. The deficits do not occur exclusively during the course of a delirium.

35 Részösszefoglalás Az amyloid béta (1-42) peptid az APP fehérje proteolitikus hasítási terméke. Aggregálódási hajlama miatt oldhatatlan extracelluláris lerakódásokat képez (plakk = amiloidózis), de már az oldható monomer is mutat neurotoxikus (szinaptotoxikus) tulajdonságokat. Az APP (Amiloid Prekurzos Protein)-nek, a 3 hasítási helynek megfelelően, 3 hasító enzimje van: alfa-szekretáz (funkcionális), béta szekretáz (diszfunkcionális/ kóros/ amiloidogén), gamma szekretáz funkcionális. A beta-szekretáz aktivitás-növekedése, és az oldható amiloid-béta peptidek megjelenése (CSF) az Alzheimer betegség kórfolyamatának legkorábbi jele. A legújabb kutatási eredmények alapján az oldhatatlan amyloid lerakódások vagy a monomer beta-amyloidok megjelenése helyett, sokkal inkább az oldható beta-amyloid oligomerek synaptikus jelenletét tartjuk neurotoxikusnak. Elvi terápiás lehetőségek: a béta-szekretáz enzim (BACE1) expressziójának akadályozása (metabolikus megközelítés), a megemelkedett béta-szekretáz enzimaktivitás gátlása (inhibítor), az amyloid béta peptidek eliminálása (immunizalás, ellenanyag, specifikus IgG)

36 neurofibrillary tangles (Tauopátia) ( dense bundles of fibers ) in the cerebral cortex: Tau fehérjék: A mikrotubulusokat stabilizáló fehérjék

37 Tau fehérjék: a mikrotubulusokat stabilizáló fehérjék Fyn is a tyrosine-specific phospho-transferase that is a member of the Src family of tyrosine protein kinases. Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase Cdk5 is also involved in the regulation of synaptic vesicle exocytosis via phosphorylation of munc-18. Cyclin-dependent kinase 5

38 Tau fehérjék: a mikorotubulusokat stabilizáló fehérjék Tau(o)pathies Taupathies are a group of neurodegenerative diseases characterised by mutations in the tau protein gene. This results in abnormal metabolism of these proteins leading to intracellular accumulation and formation of neurofibrillary tangles (NFT). These neurofibrillary tangles are deposited in the cytosol of neurons and glial cells. Examples of taupathies include: progressive supranuclear palsy (PSP) frontotemporal dementia corticobasal degeneration Pick s deseas (GSK-3) = glycogen synthase kinase-3 Frontotemporal dementia with parkinsonism-17 (FTDP-17) MAPT gene: microtubule-associated protein tau. threonine 231

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40 Propagation of Tau Misfolding from the Outside to the Inside of a Cell microtubulebinding region: MTBR C17.2 cells take up aggregated Tau. A, recombinant MTBR Tau was prepared in vitro and induced to fibrillize using arachidonic acid. Aggregated Tau is very sensitive to trypsin digestion. D, MTBR-AF488 aggregate-treated C17.2 cells with or without trypsin treatment and visualized by confocal microscopy. Scale bar, 30 μm. E, Arrows indicate displacement of tubulin.

41 *** Extracellular tau is toxic to neuronal cells Fig. 3. Toxic effect of tau variants on SH-SY5Y neuroblastoma cells. Cultured SH-SY5Y neuroblastoma cells were incubated with increasing concentrations of tau preparations, in unmodified or phosphorylated form, isolated from insect cells (overexpressing tau or the tauvlw variant). These expressed tau are present in a hyperphosphorylated form. To isolate them, in their unmodified form, the tau preparations were incubated with phosphatase λ. (A) Untreated or phosphatase treated tau samples were separated by gel electrophoresis, blotted onto nitrocellulose membranes, and probed with the AT8 (which recognizes phosphotau) and T14 (which recognizes tau independent of its phosphorylation state) antibodies. (B) The effect of unmodified tau ( ), phosphotau ( ), unmodified tauvlw ( ), phosphotauvlw (Δ) on cell viability is shown. (C) As in (B), but the effect of 5 μm tau on cell viability was tested at two different times, 24 h and 48 h. (a) tau, (b) tauvlw, (c) phosphotau, (d) phosphotauvlw. at their respective incubation time in each case.

42 *** Részösszefoglalás

43 Potenciális terápiás lehetőségek Konzervatív kezelés Béta-szekretáz inhibítorok Metabolikus beavatkozások DNS metilációs lehetőség Epigenetikai beavatkozások Immunizálás

44 alz.org

45 Konzervatív kezelés A Meynert féle bazális nukleusz (nucl. bas. Meynert) cholinerg sejtjei a neocortexbe proiciálnak. Az agykéreg cholinerg aktivitása Alzheimer (&Parkinson) betegségben erősen csökken. A csökkenés nem a Meynert féle basális magból indul ki, hanem a kergi területekről. Kolineszteráz gátlók: Ez a gyógyszercsoport, amibe a donepezil, a rivastigmine és a galantamine tartozik, úgy hat, hogy növeli az agyban a leginkább csökkenő neurotranszmitter (az információt közvetítő kémiai anyag) szintjét. A donepezil, úgy tűnik, korai stádiumú (feledékeny, de még nem demens) betegeknél, egy évvel késleltetni tudja az Alzheimer-kór előrehaladását.

46 nicotinic acetylcholine receptor (nachr) tyrosine kinase A receptor [trkar] p75 neurotrophin (p75ntr) and brain-derived neurotrophic factor (the BDNF receptor, N-methyl-D-aspartate (NMDAr) voltage-gated calcium channel (VGCC) dying back (n.bas.meynert) immunizálás long-term potentiation (LTP) long-term depression (LTD)

47 Decrease in the number of the postsynaptic marker PSD95 The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β- Mediated Synaptic Loss Wnt protein family has roles in the later development of synapse formation and plasticity. VGLUT 1 (vesicular glutamate transporter 1) Excitatory amino-acid transporters (EAATs), also known as glutamate transporters, belong to the family of neurotransmitter transporters. Glutamate is the principal excitatory neurotransmitter in the vertebrate brain. EAATs serve to terminate the excitatory signal by removal (uptake) of glutamate from the neuronal synapse into neuroglia and neurons. DKK1 has a critical role in the... proliferation and neuronal differentiation

48 Beta-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice *** We demonstrated that the injected GRL effectively enters the brain and rapidly decreases soluble Aβ in the brain of Tg2576 mice. ACI: annulus crossing index

49 4-O-Methylhonokiol is a potent CB 2 receptor ligand

50 Metabolic Dysfunction in Alzheimer s Disease and Related Neurodegenerative Disorders AD AND BODY WEIGHT ALTERATIONS IN BRAIN GLUCOSE METABOLISM IN AD Insulin and AD Leptin and AD Ghrelin and AD.

51 Statins Promote the Degradation of Extracellular Amyloid -Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion Lovastatin is lipophilic, facilitating its ability to penetrate the blood-brain barrier efficiently and influence brain levels of cholesterol (Tsuji et al., 1993).

52 An epigenetic blockade of cognitive functions in the neurodegenerating brain Nature 483, (08 March 2012) doi: /nature10849 HDAC: histone deacetylases, short hairpin RNA, AAV Increased HDAC2 is involved in silencing of genes required for learning and memory, is elevated in neurodegenerative disease such as Alzheimer Disease and it was therefore hypothesized that inhibition of HDAC2 would improve cognition which was demonstrated using shrna knockdown of HDAC2 Representative swim traces and time spent per quadrant during the water maze test (T, target quadrant; R, right; O, opposite; L, left of target). * One microlitre of shrna-containing adeno-associated viruses was stereotaxically injectedintohippocampalareaca1

53 Metiláció S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in (TRANSGENIC/APP mutant/) mice We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production.

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55 Transient Micro-needle Insertion into Hippocampus Triggers Neurogenesis and Decreases Amyloid Burden in a Mouse Model of Alzheimer s Disease Using the bregma as the reference point, a trephine hole was then drilled in the skull and the needle was gently inserted into the hippocampus (AP - 2.5mm; ML 1.3mm; DV 3.5mm) and slowly removed. The total time for insertion and removal of the micro-needle was 15 seconds.

56 Neuropsychiatr Dis Treat Feb 5;11: doi: /NDT.S ecollection The emerging role of bexarotene in the treatment of Alzheimer's disease: current evidence. Tousi B 1. Neuropharmacology Jan;100: doi: /j.neuropharm Epub 2015 May 27. Lack of support for bexarotene as a treatment for Alzheimer's disease. O'Hare E 1, Jeggo R 2, Kim EM 3, Barbour B 4, Walczak JS 5, Palmer P 6, Lyons T 7, Page D 8, Hanna D 9, Meara JR 10, Spanswick D 11, Guo JP 12, McGeer EG 12, McGeer PL 13, Hobson P 14.

57 Terápia általában Although there is currently no way to cure Alzheimer's disease or stop its progression, researchers are making encouraging advances in Alzheimer's treatment, including medications and non-drug approaches to improve symptom management. When physicians develop treatment plans, they often consider cognitive and behavioral symptoms separately. ************** Acetilkolineszteraz inhibítorok (korai kezelés): Donazepil (Aricept), galantamine (Razadyne), rivastigmine (Exelon). NMDA antagonistak (későbbi kezelés): Memantine (Memox) nem kompetitív gátlás Pszichoszociális gondozás Deseas-modifying : Anti-beta-amyloid drugs (aktív es passzív immunizaciók, Gantenerumab klinikai kipróbálás alatt) Nature Jul 30;523(7562): doi: /nature Antibody drugs for Alzheimer's show glimmers of promise. Estrogens (statisztikus hatás: valamennyire csökkentik a kockázatot) Anti-inflammatories (statisztikus hatás: valamennyire csökkentik a kockázatot)

58 Alzheimer - modellek Intrahippocampal administration of Aβ1 40 impairs spatial learning and memory in hyperglycemic mice MWM

59 Alzheimer - modellek Amyloid beta oligomer injektálása Humán Alzheimeres agyszöveti vizes extraktum injektálása Transzgénikus egér vonalak: 1/PDGF promoter expressing amyloid precursor protein (PDAPP - egér) 2/Swedish double mutant form of APP695, was introduced as the Tg2576 mouse 3/A second multi-gene PS1/APP mouse model, known as the PSAPP mouse... Teljesítmény-vizsgáló modellek 1/ Morris Water Maze 2/Radial Arm Water Maze 3/ Fear Conditioning 4/Passive-Avoidance Learning 5/Y-Maze/T-Maze 6/Object Recognition

60 Tau-modellek mice subjected to cold water stress (CWS) was made by immunoblot analyses using phosphorylation-dependent antibodies directed to eight sites on tau known to be hyperphosphorylated in the brain of Alzheimer s disease (AD) patients. Ser199, Ser202/Thr205, Thr231/Ser235 were hyperphosphorylated 20 and 40 min after CWS. Aged transgenic (Wtau-Tg) mice have greater difficulty in finding the platform in the Morris water maze (left); show less activity in the entorhinal cortex (EC) (centre); and display fewer synapses (right). Immunohis tochemical analysis using antihuman tau antibody HT7.

61 Potenciális anti-tau szerek 1 (Parkinson?) Paclitaxel: Effects of cell cycle inhibitors on tau phosphorylation in N2aTau3R cells. AR-A014418: Glycogen synthase kinase-3 (GSK-3) inhibitors reach the clinic. Thiomet-G: Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins

62 Potenciális anti-tau szerek 2 (Parkinson?) Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models: REDUCTION OF TAU PATHOLOGY AND DELAY OF DISEASE PROGRESSION ( We used antibodies PHF1 (which recognizes Tau with phosphorylated serines 396 and 404)) and MC1 (a conformation-dependent antibody that recognizes an early pathological Tau conformation) and a control mouse IgG1 In the first study we used the well characterized JNPL3 mice, which express 0N4R human Tau with the P301L mutation that causes frontotemporal dementia in humans under control of the mouse prion promoter at average levels similar to endogenous mouse Tau. These mice show an age-dependent development of neurofibrillary tangles and in later stages motor neuron loss that is associated with the onset of progressive motor dysfunction rotarod Specifikus Ab

63 Az előadás vége A többi ajánlott irodalom

64 *** Frontotemporális demencia Neuropsychiatric Inventory (NPI) delusions, hallucinations, agitation, depression (dysphoria), anxiety, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity (de: letargia is) Approximately 50% of FTD cases will present with tau pathology at post-mortem.

65 *** Positron emission tomography shows decreased cerebral blood flow in a 34-year-old male patient (left) with strokes compared with a 31-year-old male control subject (right). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) 18F-FDG PET images of vascular dementia. Hypometabolism affecting cortical, subcortical, and cerebellar areas is often seen in vascular dementia. Review : Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations

66 Plazma β-amyloid peptid szintek

67 Mol Cell Neurosci August ; 51(1-2): Amyloid precursor protein (APP) regulates synaptic structure and function

68 *** Szűrővizsgálati próbálkozások (metabolome)

69 Szűrővizsgálati próbálkozások (metabolome) This targeted analysis revealed significantly lower plasma levels of serotonin, phenylalanine, proline, lysine, phosphatidylcholine (PC), taurine and acylcarnitine (AC) in Converterpre participants who later phenoconverted to amci/ad

70 Bipolar Disord Jun;4(3): Regulation of tau phosphorylation and protection against beta-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer's disease. Alvarez G 1, Muñoz-Montaño JR, Satrústegui J, Avila J, Bogónez E, Díaz-Nido J. Author information Abstract Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of the beta-amyloid peptide and the hyperphosphorylation of the tau protein, among other features. The most widely accepted hypothesis on the etiopathogenesis of this disease proposes that the aggregates of the beta-amyloid peptide are the main triggers of tau hyperphosphorylation and the subsequent degeneration of affected neurons. In support of this view, fibrillar aggregates of synthetic beta-amyloid peptide induce tau hyperphosphorylation and cell death in cultured neurons. We have previously reported that lithium inhibits tau hyperphosphorylation and also significantly protects cultured neurons from cell death triggered by beta-amyloid peptide. As lithium is a relatively specific inhibitor of glycogen synthase kinase-3 (in comparison with other protein kinases), and other studies also point to a relevant role of this enzyme, we favor the view that glycogen synthase kinase-3 is a crucial element in the pathogenesis of Alzheimer's disease. In our opinion, the possibility of using lithium, or other inhibitors of glycogen synthase kinase-3, in experimental trials aimed to ameliorate neurodegeneration in Alzheimer's disease should be considered. +

71 *** Classification of Some Dementias Classification Characterized by β-amyloid abnormalities Characterized by tau abnormalities Examples Alzheimer's disease Frontotemporal dementia (including Pick's disease) Corticobasal ganglionic degeneration Progressive supranuclear palsy Characterized by α-synuclein abnormalities Characterized by huntington abnormalities* Vascular Lewy body dementia Dementia in patients with Parkinson's disease Huntington's disease Lacunar disease (artériák elzáródása) Binswanger's disease (fehérállomány) Multi-infarct dementia, autoimmun arteritis, Single-infarct dementia, embólia, érgörcs Due to ingestion of drugs or toxins Due to infections Due to prions Due to structural brain disorders Due to other potentially reversible disorders Alcohol-associated dementia Dementia due to exposure to heavy metals Fungal: Dementia due to cryptococcosis Spirochetal: Dementia due to syphilis or Lyme disease Viral: HIV-associated dementia, postencephalitis syndromes Creutzfeldt-Jakob disease Variant Creutzfeldt-Jakob disease Brain tumors Chronic subdural hematomas Normal-pressure hydrocephalus Depression Hypothyroidism, B12

72 *** In Vivo β-secretase 1 Inhibition Leads to Brain Aβ Lowering and Increased α-secretase Processing of Amyloid Precursor Protein without Effect on Neuregulin-1 The APP-YAC mice expressing the human WTAPP transgene.... These mice show APP expression and Aβ levels that are 2 to 3-fold above endogenous murine levels

73 *** Advances in Tau-focused drug discovery for Alzheimer's disease and related tauopathies Thus, a decrease in tau O- glycosylation could result in increased hyperphosphorylation. Tau can also be tyrosine phosphorylated37, sumoylated and nitrated38, although it is not fully understood what effects these modifica- tions have on tau

74 Potenciális anti-tau drugs 1/Anti-tau oligomers passive vaccination for the treatment of Alzheimer diseas 2/ mikrotubulusok védelme: - taxols used to treat breast cancer, - paclitaxel, inhibitor of a kinase called ERK2 reduced the excessive tau, - learning interventions and dietary intake of omega-3 fatty acids, might work partly by decreasing levels of enzymes that phosphorylate tau.

75 Dementia type Alzheimer's disease Vascular dementia Frontotemp oral dementia Dementia with Lewy bodies There is a great deal of overlap between the symptoms of various dementias. Symptoms Neuropathology Proportion of dementia cases Impaired memory, depression, poor judgement and confusion Similar to Alzheimer's disease, but memory less affected Changes in personality and mood, and difficulties with language Similar to Alzheimer's disease, also hallucinations, tremors Amyloid plaques and neurofibrillary tangles Decreased blood flow to the brain owing to a series of small strokes Damage limited to frontal and temporal lobes Cortical Lewy bodies (of the protein α-synuclein) inside neurons 50 80% 20 30% 5 10% <5% Tannic Acid is a Natural β-secretase Inhibitor that Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice