Demencia/Alzheimer

Barna István

2016. KOKI

Kísérleti Orvostudományi Kutatóintézet

barna@koki.hu

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: 24 – 30 pont

Enyhe demencia: 15 – 23 pont Közepes fokú demencia: 10 – 14 pont

Súlyos fokú demencia: < 10 pont

http://www.gvmd.hu/orvos/miniment.htm

‘REVERZIBILIS’ DEMENCIÁK Drog Emocionális betegségek (depresszió, szorongás) Metabolikus betegségek (pl. cukorbaj) Érzékszervi fogyatékosságok Neurológiai betegségek Trauma, tumor Infekció Alkoholmegvonás http://www.ttk.pte.hu/biologia/neurobio/Hallgatoknak/Neurologia/Segedanyagok/2014_osz/9_Demencia_HI_update_BZs_2014.pdf

DSM-IV: Dementia

(Diagnostic and Statistical Manual of Mental Disorders)

1. Dementia of the Alzheimer’s Type 294.10 Without behavioral disturbance

294.11 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

9. Dementia due to... [indicate other general medical condition]

Epidemiology and risk factors of dementia

De ! 65-év alatt a demenciák előfordulása statisztikailag ill. társadalmi-lag alig jelentős

Demográfia

Dementia Dementia of the Alzheimer’s Type, with early onset

294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Dementia of the Alzheimer’s Type, with late onset

294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Vascular dementia 290.40 Uncomplicated 290.41 With delirium 290.42 With delusions 290.43 With depressed mood

Dementia due to HIV disease 294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Dementia due to head trauma 294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Dementia due to Parkinson's disease 294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Dementia due to Huntington's disease 294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Dementia due to Pick’s disease 294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Dementia due to Creutzfeldt-Jakob Disease

294.10 Without behavioral disturbance 294.11 With behavioral disturbance

Dementia due to... [indicate other general medical condition]

294.10 Without behavioral disturbance 294.11 With behavioral disturbance

294.8 Dementia NOS

*** DSM

*** 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.

Alzheimer betegség

Alzheimer betegség költségvonzata Kanadában

2008 - $15 billion 2018 - $37 billion 2028 - $75 billion 2038 - $153 billion

Alzheimeresként Kvázi Alzheimeresként Összesen

BNO F00, G30 F07

Betegszám aktív ágyon 464 1671 2135

Esetszám aktív ágyon 547 1973 2520

Ápolási nap 7230 23853 31083

Költség (HBCS alapon) 63 millió Ft 240 millió Ft 303 millió Ft

2004-es ár 5000 beteg 17000 beteg

Első vizsgálat 34266 171 millió Ft 581 millió Ft

Kontroll évi 1X 4699 23 millió Ft 78 millió Ft

Házi szakápolás 2850 Ft/alkalom (10) 170 millió Ft

Magyarországon ( Skultéty László)

The Impact of Alzheimer's Disease on the Chinese Economy. 2016

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

1864

1887, MD

1889, Frankfurt am Main: the Städtische Anstalt für Irre und Epileptische

Aloysius "Alois" Alzheimer

1901, Auguste Deter, 51

1906, Auguste Deter meghal

1889, Franz Nissl

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.

***

thinning of the cerebral cortex

senile plaque (“miliary foci”)

neurofibrillary tangles (“dense bundles of fibers”) in the cerebral cortex.

The „gold standard” for Alzheimer's diagnosis

Makromorfológiai elváltozások

„thinning of the cerebral cortex”

vascular

Makromorfológiai elváltozások

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.

***

Szövettani elváltozások, senile plaque megértése

Egy kis fehérjekémia

Senile plaque megértése: amiloidózis

Betegség Fehérje aggregátum 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)

Amiloidózis

Lugol

Mol Cell Neurosci. 2012 August ; 51(1-2): 43–52.

Immunolabeling of fixed hippocampal neurons for APP

synaptotagmin 1

Amyloid Precursor Protein Is Trafficked and Secreted via Synaptic Vesicles

APP az egészséges működésű szinapszisban

amiloid prekurzor protein

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

Senile plaque (“miliary foci”) = Béta-amiloid plakk (Aβ: amyloid-β, Aβ1-42)

Direct Binding of Cholesterol to the Amyloid Precursor Protein: An Important Interaction in Lipid-Alzheimer’s Disease Relationships?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886191/

Secondary structure and membrane topology of C99 and location of the focal point for its recognition and binding of cholesterol (red-highlighted sites),

Lipid raft

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.

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

Perspektíva:

Metabolome in progression to Alzheimer's

disease

This study confirms that APP protein is a functional player in synaptic structure-functional

plasticity ... in ... neurochemical pathways.

http://www.ane.pl/pdf/6407.pdf

Metabolome vizsgálatok

http://download.springer.com/static/pdf/628/art%253A10.1007%252Fs00216-014-8102-3.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs00216-014-8102-

3&token2=exp=1457458177~acl=%2Fstatic%2Fpdf%2F628%2Fart%25253A10.1007%25252Fs00216-014-8102-

3.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs00216-014-8102-3*~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.

Using direct infusion mass spectrometry for serum metabolomics in Alzheimer’s disease

November 2014, Volume 406, Issue 28, pp 7137-7148

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

DOI: http://dx.doi.org/10.1093/brain/awu255 awu255 First published online: 10 September 2014

http://www.nature.com/news/more-evidence-emerges-for-transmissible-alzheimer-s-theory-1.19229

(2016)

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].

http://www.sciencedirect.com/science/article/pii/S000294401065184X

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.

***

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)

„neurofibrillary tangles” (Tauopátia)

(“dense bundles of fibers”)

in the cerebral cortex:

Tau fehérjék:

A mikrotubulusokat stabilizáló fehérjék

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

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

Frontotemporal dementia with parkinsonism-17 (FTDP-17)

MAPT gene: “microtubule-associated protein tau.”

(GSK-3) = glycogen synthase kinase-3

threonine 231

http://onlinelibrary.wiley.com/doi/10.1002/ange.200802621/full

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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676015/?tool=pubmed

Propagation of Tau Misfolding from the Outside to the Inside of a Cell

microtubule- binding region: MTBR

Extracellular tau is toxic to neuronal cells http://www.sciencedirect.com/science/article/pii/S001457930600946X

***

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.

Részösszefoglalás

***

Potenciális terápiás lehetőségek

Konzervatív kezelés

Béta-szekretáz inhibítorok

Metabolikus beavatkozások

DNS metilációs lehetőség

Epigenetikai beavatkozások

Immunizálás

http://www.sciencedirect.com/science/article/pii/S0001299811000341

alz.org

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.

http://jnm.snmjournals.org/content/47/2/302.full.pdf+html

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.

Konzervatív kezelés

N-methyl-D-aspartate (NMDAr) voltage-gated calcium channel (VGCC)

nicotinic acetylcholine receptor (nAChr)

tyrosine kinase A receptor [trkAr]

long-term potentiation (LTP)

long-term depression (LTD)

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/L/LTP.html

p75 neurotrophin (p75NTr) and brain-derived neurotrophic factor (the BDNF receptor,

„dying back” (n.bas.Meynert)

immunizálás

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

http://www.jneurosci.org/content/32/10/3492.long

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

http://toxsci.oxfordjournals.org/content/125/2/488.full

Wnt protein family has roles in the later development of synapse formation and plasticity.

Decrease in the number of the postsynaptic marker PSD95

Beta-Secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice

*** We demonstrated that the injected GRL-

8234 effectively enters the brain and rapidly decreases

soluble Aβ in the brain of Tg2576 mice.

ACI: annulus crossing index

4-O-Methylhonokiol is a potent CB2 receptor ligand

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….

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). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666925/

http://www.ncbi.nlm.nih.gov/pubmed/20876579

An epigenetic blockade of cognitive functions in the neurodegenerating brain Nature 483, 222–226 (08 March 2012) doi:10.1038/nature10849

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

HDAC: histone deacetylases, short hairpin RNA, AAV

One microlitre of shRNA-containing adeno-associated viruses was stereotaxically injectedintohippocampalareaCA1

Representative swim traces and time spent per quadrant during the water maze test (T, target quadrant; R, right; O, opposite; L, left of target). *

S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in (TRANSGENIC/APP mutant/) mice

http://www.sciencedirect.com/science/article/pii/S0197458011005458

We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin

deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production.

Metiláció

Transient Micro-needle Insertion into Hippocampus Triggers Neurogenesis and Decreases Amyloid Burden in a Mouse

Model of Alzheimer’s Disease http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-CT-1541_Song_et_al

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.

Neuropsychiatr Dis Treat. 2015 Feb 5;11:311-5. doi: 10.2147/NDT.S61309. eCollection 2015. The emerging role of bexarotene in the treatment of Alzheimer's disease: current evidence. Tousi B1.

Neuropharmacology. 2016 Jan;100:124-30. doi: 10.1016/j.neuropharm.2015.04.020. Epub 2015 May 27. Lack of support for bexarotene as a treatment for Alzheimer's disease. O'Hare E1, Jeggo R2, Kim EM3, Barbour B4, Walczak JS5, Palmer P6, Lyons T7, Page D8, Hanna D9, Meara JR10, Spanswick D11, Guo JP12, McGeer EG12, McGeer PL13, Hobson P14.

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. 2015 Jul 30;523(7562):509-10. doi: 10.1038/nature.2015.18031.

Antibody drugs for Alzheimer's show glimmers of promise.

Estrogens (statisztikus hatás: valamennyire csökkentik a kockázatot)

Anti-inflammatories (statisztikus hatás: valamennyire csökkentik a kockázatot)

Alzheimer - modellek

Intrahippocampal administration of Aβ1–40 impairs spatial learning and memory in hyperglycemic mice

MWM

http://www.sciencedirect.com/science/article/pii/S1074742706001626

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

http://www.ncbi.nlm.nih.gov/books/NBK5231/

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. http://www.sciencedirect.com/science/article/pii/S0014579302038838

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). http://www.rikenresearch.riken.jp/eng/research/5200

http://www.nature.com/emboj/journal/v26/n24/pdf/7601917a.pdf

Immunohistochemical analysis using anti-human tau antibody HT7.

Potenciális anti-Tau szerek 1 (Parkinson?)

Thiomet-G: Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins

Paclitaxel: Effects of cell cycle inhibitors on tau phosphorylation in N2aTau3R cells.

AR-A014418: Glycogen synthase kinase-3 (GSK-3) inhibitors reach the clinic.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787232/?tool=pubmed

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 (http://www.jbc.org/content/286/39/34457.long)

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

rotarod

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

Specifikus Ab

Az előadás vége

A többi „ajánlott irodalom”

Frontotemporális demencia

delusions, hallucinations, agitation, de- pression (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.

Neuropsychiatric Inventory (NPI)

***

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).

18F-FDG PET images of vascular dementia. Hypometabolism affecting cortical, subcortical, and cerebellar areas is often seen in vascular dementia.

CADASIL (cerebral autosomal dominant

arteriopathy with subcortical infarcts and

leukoencephalopathy)

Review : Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations http://jnnp.bmj.com/content/82/2/126.full

***

http://www.nature.com/articles/srep06777

http://www.sciencedirect.com/science/article/pii/S0197458006000893

2006

Plazma β-Amyloid peptid szintek

Mol Cell Neurosci. 2012 August ; 51(1-2): 43–52.

Amyloid precursor protein (APP) regulates synaptic structure and function

Groemer TW, Thiel CS, Holt M, Riedel D, Hua Y, et al. (2011) Amyloid Precursor Protein Is Trafficked and Secreted via Synaptic Vesicles. PLoS ONE 6(4): e18754. doi:10.1371/journal.pone.0018754 http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0018754

*** Szűrővizsgálati próbálkozások

(metabolome)

http://www.nature.com/nm/journal/v20/n4/pdf/nm.3466.pdf

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 „

Bipolar Disord. 2002 Jun;4(3):153-65. Regulation of tau phosphorylation and protection against beta-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer's disease. Alvarez G1, 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. + http://primarypsychiatry.com/wp-content/uploads/import/0709PP_Desai.pdf

Classification of Some Dementias

Classification Examples

Characterized by β-amyloid abnormalities Alzheimer's disease

Characterized by tau abnormalities Frontotemporal dementia (including Pick's disease)

Corticobasal ganglionic degeneration

Progressive supranuclear palsy

Characterized by α-synuclein abnormalities Lewy body dementia

Dementia in patients with Parkinson's disease

Characterized by huntington abnormalities* Huntington's disease

Vascular 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 Alcohol-associated dementia

Dementia due to exposure to heavy metals

Due to infections Fungal: Dementia due to cryptococcosis

Spirochetal: Dementia due to syphilis or Lyme disease

Viral: HIV-associated dementia, postencephalitis

syndromes

Due to prions Creutzfeldt-Jakob disease

Variant Creutzfeldt-Jakob disease

Due to structural brain disorders Brain tumors

Chronic subdural hematomas

Normal-pressure hydrocephalus

Due to other potentially reversible disorders Depression

Hypothyroidism, B12

***

http://jpet.aspetjournals.org/content/324/3/957.full

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

***

Advances in Tau-focused drug discovery for Alzheimer's disease and related tauopathies http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787232/?tool=pubmed

***

Thus, a decrease in tau O-glycosylation could result in

increased hyperphos- phorylation. Tau can also

be tyrosine phospho- rylated37, sumoylated and nitrated38, although it is not fully understood what

effects these modifica-

tions have on tau

Potenciális anti-Tau drugs 1/Anti-tau oligomers passive vaccination for the treatment of Alzheimer diseas http://www.landesbioscience.com/journals/vaccines/KayedHV6-11.pdf

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. http://www.sciencemag.org/content/316/5830/1416.full.pdf

There is a great deal of overlap between the symptoms of various dementias.

Dementia

type

Symptoms Neuropathology Proportion

of dementia

cases

Alzheimer's

disease

Impaired memory,

depression, poor judgement

and confusion

Amyloid plaques and

neurofibrillary tangles 50–80%

Vascular

dementia

Similar to Alzheimer's

disease, but memory less

affected

Decreased blood flow to the

brain owing to a series of

small strokes

20–30%

Frontotemp

oral

dementia

Changes in personality and

mood, and difficulties with

language

Damage limited to frontal

and temporal lobes 5–10%

Dementia

with Lewy

bodies

Similar to Alzheimer's

disease, also hallucinations,

tremors

Cortical Lewy bodies (of the

protein α-synuclein) inside

neurons

<5%

Tannic Acid is a Natural β-secretase Inhibitor that Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice http://www.jbc.org/content/early/2012/01/04/jbc.M111.294025.long