Сергеева Марина Глебовна, нии фхб им. А. Н. Белозерского мгу e-mail: Москва, 2008 Оглавление тезисы

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Yun-wu Zhang
Hui Zheng
Chad A Dickey
Hyang-Sook Hoe
Ismael Santa-Maria
Sarah L Cole
Tara L. Spires and Bradley T. Hyman
6. Признаки перечисленных когнитивных нарушений должны выявляться вне состояний помрачения сознания. 7.
Характеристики белков, участвующих в патогенезе болезни Альцгеймера

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Kulandaivelu S Vetrivel¹, Yun-wu Zhang², Huaxi Xu² and Gopal Thinakaran¹

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[11] - The amyloid precursor protein: beyond amyloid

Hui Zheng^1,2 and Edward H Koo^1,2

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[12] - Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression

Chad A Dickey, Peter Ash, Natalia Klosak, Wing C Lee, Leonard Petrucelli, Michael Hutton and Christopher B Eckman

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[13] - Apolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons

Hyang-Sook Hoe, Jacob Freeman and G William Rebeck

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[14] - Tramiprosate, a drug of potential interest for the treatment of Alzheimer's disease, promotes an abnormal aggregation of tau

Ismael Santa-Maria¹, Félix Hernández¹, Joaquín Del Rio^2,3, Francisco J Moreno¹ and Jesús Avila^1,3

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[15] - The Alzheimer's disease β-secretase enzyme, BACE1

Sarah L Cole and Robert Vassar

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[16] - Transgenic Models of Alzheimer's Disease: Learning from Animals

Tara L. Spires and Bradley T. Hyman

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Приложения

Приложение 1. Критерии прижизненного диагноза болезни Альцгеймера


   1. Наличие синдрома деменции.
   2. Развитие множественного дефицита познавательных функций, который определяется сочетанием расстройств памяти с ухудшением запоминания новой и/или воспроизведения ранее усвоенной информации и присутствием признаков по крайней мере одного из следующих когнитивных нарушений: афазии (нарушение речевой функции), апраксии (нарушение способности к выполнению двигательной активности, несмотря на ненарушенные моторные функции); агнозии (невозможность распознавать или идентифицировать объекты, несмотря на сохранное сенсорное восприятие); нарушений собственно интеллектуальной деятельности, т.е. планирования и программирования деятельности, абстрагирования, установления причинно-следственных связей и др.
   3. Нарушения как памяти, так и когнитивных функций должны быть выражены настолько, чтобы вызывать снижение социальной или профессиональной адаптации больного по сравнению с ее прежним уровнем.
   4. Течение характеризуется постепенным малозаметным началом и неуклонным прогрессированием нарушений когнитивных функций.
   5. Отсутствуют данные клинического или специальных параклинических исследований, которые могли бы указать на то, что расстройства памяти и когнитивных функций обусловлены каким-либо другим заболеванием или повреждением центральной нервной системы (например, церебрально-сосудистым заболеванием, болезнью Паркинсона или Пика, хореей Гентингтона, субдуральной гематомой, гидроцефалией и др.), системным заболеванием, о котором известно, что оно может вызывать синдром деменции (например, гипотиреоидизм, недостаточность витамина В12 или фолиевой кислоты, гиперкальциемия, нейросифилис, ВИЧ-инфекция, тяжелая органная недостаточность и др.) или состоянием интоксикации (в том числе медикаментозной).
    6. Признаки перечисленных когнитивных нарушений должны выявляться вне состояний помрачения сознания.
   7. Анамнестические сведения и данные клинического исследования исключают связь выявляемых расстройств когнитивных функций с каким-либо другим психическим заболеванием (например, с депрессией, шизофренией, умственной отсталостью и др.).

Приложение 2. Характеристики белков, участвующих в патогенезе болезни Альцгеймера

Данные получены с помощью БД SwissProt. Отдельными цветами выделены семейства:

PROT	AC	GENE	DISEASE	FUNCTION	RELATION TO AD	TISSUE	FAMILY
A4	P05067	APP	AD	Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1/Tip60 and inhibit Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with overexpressed HADH2 leads to oxidative stress and neurotoxicity.	Defects in APP are a cause of autosomal dominant Alzheimer disease (AD) [MIM:ссылка скрыта]. AD is the most prevelant form of dementia, characterized by neurofibrillary tangles and amyloid plaques deposition in the brain. Identical lesions occur in the neurons of aged Down syndrome but at an earlier age than in AD. The major constituent of these neuritic plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. Mutations occurring at the beta-amyloid N-terminal, such as the Swedish double mutation, appear to increase levels of beta-amyloid by facilitating beta-secretase cleavage resulting in elevated levels of both beta-APP42 and beta-APP40. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31, are also implicated in AD neuronal death. Alzheimer disease caused by mutations in APP is a rare occurrence and usually causes the familial or early-onset form of the disease (FAD). Flemish-type AD is characterized by, in addition to presenile dementia, cerebral hemorrhaging due to cerebral amyloid angiopathy which is similar to, but distinct from, cerebroarterial amyloidosis Dutch type. Only about 5% of all cases of Alzheimer disease are caused by FAD mutations, the rest are sporadic.	Expressed in all fetal tissues examined with highest levels in brain, kidney, heart and spleen. Weak expression in liver. In adult brain, highest expression found in the frontal lobe of the cortex and in the anterior perisylvian cortex- opercular gyri. Moderate expression in the cerebellar cortex, the posterior perisylvian cortex-opercular gyri and the temporal associated cortex. Weak expression found in the striate, extra- striate and motor cortices. Isoform APP695 is the predominant form in neuronal tissue, isoform APP751 and isoform APP770 are widely expressed in non-neuronal cells. Isoform APP751 is the most abundant form in T-lymphocytes. Appican is expressed in astrocytes.
AACT	P01011	Начало формы SERPINA3 Конец формы	Начало формы COPD Конец формы	can inhibit neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2	Found in the myloid plaques from the hippocampus of Alzheimer's disease brains	KIDNEY	SERPINA
AATF	Q9NY61	AATF		May function as a general inhibitor of the histone deacetylase HDAC1. Binding to the pocket region of RB1 may displace HDAC1 from RB1/E2F complexes, leading to activation of E2F target genes and cell cycle progression. Conversely, displacement of HDAC1 from SP1 bound to the CDKN1A promoter leads to increased expression of this CDK inhibitor and blocks cell cycle progression May also bind MAPT	antagonizes PAWR mediated induction of aberrant amyloid peptide production in Alzheimer disease (presenile and senile dementia), although the molecular basis for this phenomenon has not been described to date.	brain, heart, kidney, placenta and thymus	AATF
Abi-1	Q81ZP0	ABI1	acute leukemias	May act in negative regulation of cell growth and transformation by interacting with nonreceptor tyrosine kinases ABL1 and/or ABL2. May play a role in regulation of EGF-induced Erk pathway activation. Involved in cytoskeletal reorganization and EGFR signaling. Together with EPS8 participates in transduction of signals from Ras to Rac. In vitro, a trimeric complex of ABI1, EPS8 and SOS1 exhibits Rac specific guanine nucleotide exchange factor (GEF) activity and ABI1 seems to act as an adapter in the complex. Regulates ABL1/c-Abl-mediated phosphorylation of MENA. Recruits WASF1 to lamellipodia and there seems to regulate WASF1 protein level (By similarity).	localized to neuronal growth cones and synaptosomes (By similarity).	BRAIN	ABI
ACOT2	P49753	ACOT2		Acyl-CoA thioesterases are a group of enzymes that catalyze the hydrolysis of acyl-CoAs to the free fatty acid and coenzyme A (CoASH), providing the potential to regulate intracellular levels of acyl-CoAs, free fatty acids and CoASH. Displays high levels of activity on medium- and long chain acyl CoAs.		heart, liver, muscle and kidney. Weak in placenta and pancreas.	C/M/P thioester hydrolase family
APOE	P02649	APOE	familial dysbetalipoproteinemia CAD AD	Mediates the binding, internalization, and catabolism of lipoprotein particles. It can serve as a ligand for the LDL (apo B/E) receptor and for the specific apo-E receptor (chylomicron remnant) of hepatic tissues.	The APOE4 allele is associated with late onset Alzheimer disease 2 (AD2) [MIM:ссылка скрыта]. The APOE4 allele is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE4 alleles in 42 families with late onset AD. Thus APOE4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE4 was virtually sufficient to cause AD by age 80. The mechanism by which APOE4 participates in pathogenesis is not known.	Occurs in all lipoprotein fractions in plasma. It constitutes 10-20% of very low density lipoproteins (VLDL) and 1-2% of high density lipoproteins (HDL). APOE is produced in most organs. Significant quantities are produced in liver, brain, spleen, lung, adrenal, ovary, kidney and muscle.
ASAH2	Q9NR71	ASAH2		Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid at an optimal pH of 6.5-8.5. Acts as a key regulator of sphingolipid signaling metabolites by generating sphingosine at the cell surface. Acts as a repressor of apoptosis both by reducing C16-ceramide, thereby preventing ceramide-induced apoptosis, and generating sphingosine, a precursor of the antiapoptotic factor sphingosine 1-phosphate. Probably involved in the digestion of dietary sphingolipids in intestine by acting as a key enzyme for the catabolism of dietary sphingolipids and regulating the levels of bioactive sphingolipid metabolites in the intestinal tract.		Intestine, kidney, skeletal muscle and heart	neutral ceramidase
ATS4	O75173	ADAMTS4	arthritic diseases, Alzheimer	Cleaves aggrecan, a cartilage proteoglycan, and may be involved in its turnover. May play an important role in the destruction of aggrecan in arthritic diseases.	Could also be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease	brain, lung and heart, low level in placenta and skeletal muscles	Glutamyl endopeptidase
BACE1	P56817	BACE1	Alzheimer	Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.	Broad endopeptidase specificity. Cleaves Glu- Val-Asn-Leu-\|-Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein.	Brain	peptidase A1
BACE2	Q9Y5Z0	BACE2	Alzheimer	Single-pass type I membrane protein	Broad endopeptidase specificity. Cleaves Glu- Val-Asn-Leu-\|-Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein.		peptidase A1
BPTF	Q12830	BPTF		Histone-binding component of NURF (nucleosome-remodeling factor), a complex which catalyzes ATP-dependent nucleosome sliding and facilitates transcription of chromatin. Specifically recognizes H3 tails trimethylated on 'Lys-4' (H3-K4Me3), which mark transcription start sites of virtually all active genes. May also regulate transcription through direct binding to DNA or transcription factors.	Expressed at low levels in adult brain and spinal cord and reexpressed in neurodegenerative diseases (at protein level).	Testis, kidney, liver and brain - highest levels are found in motor cortex (at protein level).	PBTF
CATD	P07339	CTSD	neuronal ceroid lipofuscinosis 10 (CLN10), also known as neuronal ceroid lipofuscinosis due to cathepsin D deficiency. The neuronal ceroid lipofuscinosis are a group of progressive neurodegenerative diseases in children and in adults, characterized by visual and mental decline, motor disturbance, epilepsy and behavioral changes.	Acid protease active in intracellular protein breakdown.	The Val-58 allele is significantly overrepresented in demented patients (11.8%) compared with non-demented controls (4.9%). Carriers of the Val-58 allele have a 3.1-fold increased risk for developing AD than non-carriers. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease.		peptidase A1
CD5R1	Q15078	CDK5R1	Alzheimer	p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Activator of TPKII.	Cleavage of p35 to p25 may be involved in the pathogenesis of Alzheimer disease. The p25 form accumulates in neurons in the brain of patients with Alzheimer disease, but not in normal brain. This accumulation correlates with an increase in CDK5 kinase activity. Application of amyloid beta peptide A- beta(1-42) induced the conversion of p35 to p25 in primary cortical neurons. Expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis.	Brain and neuron specific.	cyclin-dependent kinase 5 activator
CH25H	O95992	CH25H	Alzheimer	Catalyzes the formation of 25-hydroxycholesterol from cholesterol, leading to repress cholesterol biosynthetic enzymes. May play an important role in regulating lipid metabolism by synthesizing a corepressor that blocks sterol regulatory element binding protein (SREBP) processing. In testis, production of 25- hydroxycholesterol by macrophages may play a role in Leydig cell differentiation.	Not associated with susceptibility to Alzheimer disease.		sterol desaturase
CIB1	Q99828	CIB1		May convert the inactive conformation of integrin alpha- IIb/beta3 to an active form through the binding to the integrin cytoplasmic domain.	Interacts with the protein kinases PLK2/SNK and with the region immediately upstream of the kinase domain of DNA-PK. Interacts with PSEN2.	Ubiquitous
CLUS	P10909	CLU		Not yet clear. It is known to be expressed in a variety of tissues and it seems to be able to bind to cells, membranes and hydrophobic proteins. It has been associated with programmed cell death (apoptosis).			clusterin
COL12	Q5KU26	COLEC12	Alzheimer	Scavenger receptor that displays several functions associated with host defense. Promotes binding and phagocytosis of Gram-positive, Gram-negative bacteria and yeast. Mediates the recognition, internalization and degradation of oxidatively modified low density lipoprotein (oxLDL) by vascular endothelial cells. Binds to several carbohydrates including Gal-type ligands, D-galactose, L- and D-fucose, GalNAc, T and Tn antigens in a calcium-dependent manner and internalizes specifically GalNAc in nurse-like cells. Binds also to sialyl Lewis X or a trisaccharide and asialo-orosomucoid (ASOR). in the temporal cortex of Alzheimer patient (at protein level), Expressed in reactive astrocytes and vascular/perivascular cells in the brain of Alzheimer patient.	May also play a role in the clearance of amyloid beta in Alzheimer disease. The extracellular domain forms a stable trimer. The extracellular domain interacts with fibrillar beta amyloid peptide.	perivascular macrophages, plaques-surrounding reactive astrocytes and in perivascular astrocytes associated with cerebral amyloid angiopathy (CAA), placenta, heart, skeletal muscle, small intestine and lung. brain, colon, thymus and kidney. nurse-like cells.
COPA1	Q9BXSO	COL25A1	Alzheimer	Inhibits fibrillization of beta amyloid peptide during the elongation phase. Has also been shown to assemble amyloid fibrils into protease-resistant aggregates. Binds heparin. Binds to the fibrillized forms of beta amyloid peptide 40 (beta-APP40) and beta amyloid peptide 42 (beta-APP42). Found associated with beta-APP42 more frequently than with beta-APP40.	Deposited preferentially in primitive or neuritic amyloid plaques which are typical of Alzheimer's disease. Undergoes proteolytic cleavage by furin protease to yield the soluble collagen-like Alzheimer amyloid plaque component.	brain.
CSEN	Q9Y2N7	KCNIP3	Alzheimer	Calcium-dependent transcriptional repressor that binds to the DRE element of genes including PDYN and FOS. Affinity for DNA is reduced upon binding to calcium and enhanced by binding to magnesium. Seems to be involved in nociception (By similarity). Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. Probably modulates channels density, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. In vitro, modulates KCND2/Kv4.2 and KCND3/Kv4.3 currents. Involved in KCND2 and probably KCND3 trafficking to the cell surface. May play a role in the regulation of PSEN2 proteolytic processing and apoptosis. Together with PSEN2 involved in modulation of beta-amyloid formation.	Expression levels are elevated in brain cortex regions affected by Alzheimer disease.	brain	recoverin

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Сергеева Марина Глебовна, нии фхб им. А. Н. Белозерского мгу e-mail: Москва, 2008 Оглавление тезисы

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