Роль липидов в процессах нейропластичности и нейродегенерации тема диссертации и автореферата по ВАК РФ 03.00.04, доктор биологических наук Кудинов, Алексей Рудольфович

• Кудинов, Алексей Рудольфович
• доктор биологических наук
• 2007

Оглавление диссертации доктор биологических наук Кудинов, Алексей Рудольфович

ГЛАВА 1.

ВВЕДЕНИЕ.

1.1. Актуальность работы.

1.2. Цель и задачи исследования.

1.3.Положения, выносимые на защиту.

1 АНаучная новизна работы.

1.5. Научно-практическая значимость работы.

ГЛАВА 2.

СОВРЕМЕННЫЕ ПРЕДСТАВЛЕНИЯ О РОЛИ ЛИПИДОВ В НЕЙРОДЕГЕНЕРАТИВНЫХ ЗАБОЛЕВАНИЯХ (ОБЗОР ЛИТЕРАТУРЫ).

2.1. ХОЛЕСТЕРИН И ЕГО ОБМЕН В ЖИВОТНОМ ОРГАНИЗМЕ.

2.1.1. Биохимия холестерина.

2.1.2. Распределение холестерина в животном организме.

2.2. ХОЛЕСТЕРИН И ФОСФОЛИПИДЫ В СТРУКТУРЕ МЕМБРАН.

2.2.1. Холестерин и фосфолипиды в строении клеточной мембраны.

2.2.2. Микродомены в плазматической мембране.

2.2.2.1 .Клатрин-окаймленные ямки.

2.2.2.2. Кавеолы.

2.2.3. ПЕРЕКИСНОЕ ОКИСЛЕНИЕ ЛИПИДОВ В СТРУКТУРЕ МЕМБРАН.

2.2.3.1. Первичные радикалы.

2.2.3.2. Активные формы кислорода.

2.2.3.3. Цепное окисление липидов.

2.2.3.4. Биологические последствия ПОЛ.

2.2.3.5. Регуляция ПОЛ.

2.2.3.6. Водорастворимые антиоксиданты.

2.2.3.7. Липидные антиоксиданты.

2.3. ГОМЕОСТАЗ ХОЛЕСТЕРИНА В КЛЕТКЕ.

2.3.1. Захват холестерина.

2.3.2. Биосинтез холестерина.

2.3.3. Регулирование биосинтеза холестерина.

2.3.4. Транспорт холестерина из клетки.

2.3.5. Холестерин модулирует внутриклеточный липидный транспорт.

2.4. ХОЛЕСТЕРИН В ТКАНИ МОЗГА.

2.4.1. Ano Е, холестерин и нейромышечные болезни.

2.4.2. Болезнь Нимана Пика тип С, холестерин и нейродегенерация.

2.4.3. Синдром Дауна и другие наследственные заболевания.

2.5. ЭЛЕКТРОФИЗИОЛОГИЧЕСКИЙ АНАЛИЗ СРЕЗОВ МОЗГА-НЕЙРОПЛАСТИЧНОСТЬ И ДОЛГОСРОЧНАЯ ПОТЕНЦИАЦИЯ.

2.5.1. Анализ нейропластичности: долгосрочная потенциация.

2.5.2. Почему электрофизиологическая запись в гиппокампе.

2.6. МОРФОЛОГИЧЕСКИЕ ПРИЗНАКИ НЕЙРОДЕГЕНЕРАЦИИ.

2.6.1. Амилоид бета. Формирование амилоидных бляшек.

2.6.2. АР, ПБА, холестерин, и нейромышечные патологии.

2.6.3. Амилоид р, нормальный функциональный белок организма?.

2.6.2. Белок тау. Образование нейрофибриллярных клубков.

ГЛАВА 3.

ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ.

3.1. ИЗУЧЕНИЕ ХОЛЕСТЕРИНА И ФОСФОЛИПИДОВ

В СРЕЗАХ ГИППОКАМПА КРЫСЫ.

3.1.1. Животные.

3.1.2. Реактивы.

3.1.3. Методы.

3.1.3.1. Приготовление срезов гиппокампа.

3.1.3.2. Метаболическое мечение липидов срезов гиппокампа.

3.1.3.3. Авторская инкубационная камера для срезов.

3.2. БИОХИМИЧЕКИЙ АНАЛИЗ ЛИПИДОВ МОЗГА.

3.2.1. Изучение синтеза липидов в ткани гиппокампа.

3.2.2. Радиоавтографический анализ срезов гиппокампа.

3.3. ИММУНОГИСТОХИМИЧЕКИЙ АНАЛИЗ СРЕЗОВ ГИППОКАМПА.

3.4. ЭЛЕКТРОФИЗИОЛОГИЧЕСКИЙ АНАЛИЗ СРЕЗОВ ГИППОКАМПА.

3.4.1. Регистрация ВПСП, ДП и парного усиления.

3.4.2. Обработка данных и статистический анализ.

3.4.3. Экспериментальная установка для двухканальной записи.

3.4.4. Изучение поведения лабораторных крыс.

3.5. БИОХИМИЧЕСКИЙ АНАЛИЗ ПРОДУКТОВ ПОЛ.

ГЛАВА 4. РЕЗУЛЬТАТЫ.

4.1. ИЗУЧЕНИЕ РОЛИ ХОЛЕСТЕРИНА И ФОСФОЛИПИДОВ В НЕЙРОПЛАСТИЧНОСТИ НЕЙРОНОВ.

4.1.1. Биохимический и гистохимический анализ холестерина и фосфолипидов срезов гиппокампа.

4.1.2. «Острый» дисбаланс холестерина и фосфолипидов вызывает нейро-дегенерацию в гиппокампе.

4.1.3. Холестерин, фосфолипиды и нейропластичность.

4.1.3.1. Роль в инициации и поддержании ДП.

4.1.3.2. Роль в пресинаптическом компоненте нейротрансмиссии.

4.1.4. Острая модуляция липидов гиппокампа не влияет на Aß.

4.2. ИЗУЧЕНИЕ КРЫС СОДЕРЖАЩИХСЯ НА ДИЕТЕ С ПОВЫШЕННЫМ СОДЕРЖАНИЕМ ХОЛЕСТЕРИНА.

4.2.1. Хроническое повышение холестерина в пище приводит к отложению амилоида ß в ткани мозга крыс.

4.2.2. Диета с повышенным холестерином пищи вызывает нарушение поведения лабораторных крыс.

4.2.3. Диета с повышенным холестерином вызывает нарушение долгосрочной потенциации в гиппокампе крыс.

4.2.4. Пищевой холестерин усиливает синтез собственного холестерина в ткане мозге.

4.3. ИЗУЧЕНИЕ ВЛИЯНИЯ ОКСИДАТИВНЫХ РЕАКЦИЙ И ПЕРЕКИСНОГО ОКИСЛЕНИЯ ЛИПИДОВ (ПОЛ) НА НЕЙРОПЛАСТИЧНОСТЬ.

4.3.1. Перекись водорода модулирует нейропластичность.

4.3.2. ПОЛ модулирует нейропластичность.

4.4. ВЛИЯНИЕ АМИЛОИДА БЕТА И НЕЙРОПЛАСТИЧНОСТИ НА МЕТАБОЛИЗМ ЛИПИДОВ.

4.4.1. Амилоид бета и метаболизм липидов в ткани мозга.

4.4.2. Влияние нейропластичности на синтез липидов в гиппокампе.

4.4.3. Амилоид бета, холестерин и нейропластичность,

ГЛАВА 5.

ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ.

5.1. ЛИПИДЫ И СИНАПТИЧЕСКАЯ НЕЙРОПЛАСТИЧНОСТЬ.

5.1.1. Экспериментальная система острой модуляции липидов гиппокампа крысы.

5.1.2. Биохимический анализ динамики холестерина и фосфолипидов в срезах гиппокампа.

5.1.3. Липиды важны для синаптической пластичности и нейротрансмиссии.

5.2. ЛИПИДЫ И ДЕГЕНЕРАЦИЯ ЦИТОСКЕЛЕТА.

5.3. ЛИПИДЫ, НЕЙРОПЛАСТИЧНОСТЬ, Ар и БА.

5.3.1. Холестерин и болезнь Альцгеймера.

5.3.2. «Хроническая» модуляция холестерина вызывает нарушение нейропластичности и нейродегенерацию.

5.4. ОКСИДАТИВНЫЕ РЕАКЦИИ, ПОЛ И НЕЙРОПЛАСТИЧНОСТЬ.

5.4.1. Перекись водорода и нейропластичность.

5.4.2. Перекисное окисление липидов (ПОЛ) и нейропластичность.

5.5. АМИЛОИД БЕТА - ФУНКЦИОНАЛЬНЫЙ БЕЛОК?.

5.5.1. Амилоид бета, нейропластичность и липиды.

5.5.2. Ар и ПБА - интегрированная система для регулирования холестерина и динамики мембран ейронов.

5.6. НАРУШЕНИЕ БИОХИМИИ ХОЛЕСТЕРИНА - ПЕРВИЧНАЯ ПРИЧИНА НЕЙРОДЕГЕНЕРАЦИИ?.

5.6.1. Холестерин и признаки нейродегенерации.

5.6.2. Наложение характеристических черт нейродегенерации при разных нейродегенеративных болезнях.

5.6.3. Какова первичная причина нейродегенерации?.

5.6.4. Холестерин, нейродегенерация и химическая специфичность нейротрансмиссии.

ГЛАВА 6.

Введение диссертации (часть автореферата) на тему «Роль липидов в процессах нейропластичности и нейродегенерации»

За последние десятилетие медико-биологической науке существенно возрос интерес к проблеме взаимосвязи биохимии липидов и целого ряда нейродегенеративных заболеваний, таких как болезнь Альцгеймера (БД), Синдром Дауна, болезнь Пимана Пика Тип С (НПС), нейромышечные патологии. Болезнь Альцгеймера относится к группе патологий старческого возраста и является четвертой причиной смертности развитых стран после сердечно-сосудистых в большинстве и раковых заболеваний. Напротив, Синдром Дауна и болезнь Нимана Пика тип С поражают в детском возрасте. Несмотря на это основные морфобиологические перечисленных отложения болезней почти бета идентичны. (АР) и Это характеристики внеклеточные белка-амилоида внутри наличие нейрофибриллярных клубков нейронов, обусловленных избыточным фосфорилированием белка тау, в норме ассоциированого с микротрубочками. В течение длительного времени в научной литературе существовало мнение, что главной причиной нейродегенарции при болезни Альцгеймера и синдроме Дауна являются отложения в ткани мозга амилоида бета. Считалось, что Ар, является состоящий из 39-43 аминокислотных остатков патологическим продуктом своего исключительно предшественника (ПБА) трансмембранного гликопротеина, ген которого локализован на 21 хромосоме. Однако, в 1992 году АР был обнаружен в плазме крови и спинномозговой жидкости (СМЖ) здоровых доноров, а также в культуральных средах многих клеточных линий в растворенной, неаггрегированной форме (1-3). Более того, в собственных новаторских исследованиях автора и его коллег (4-11) было показано, что в плазме крови, СМЖ и культуральной среде клеток печени HepG2 АР ассоциирован с липопротеинами высокой плотности (ЛВП). Это было позднее подтверждено другими научными группами (12-13). Десять лет назад автором было высказано предположение, что, как и многие другие белки липопротеинов (называемые апобелками или аполипопротеинами). Ар имеет функции, связанные с обменом липидов. Некоторые из таких возможных функций были обнаружены автором и его коллегами, в частности, ингибирование этерификации холестерина (ХС) в плазме крови (14-15) и снижение синтеза липидов в культуре клеток печени человека (16-17). Дальнейшее изучение биохимической роли Ар в метаболизме липидов, в частности в переживающих срезах являлось одним из направлений данной работы. Важно заметить, что причинные факторы изменения биологии АР и белка тау при болезни Альцгеймера и других патологических состояниях остаются все еще не раскрытыми (4,5). Возможно, что подобные гиппокампа крысы, Исследования ассоциации амилоида бета с липопротеинами были представлены в диссертации Кудинова А.Р. на соискание ученой степени кандидата биологических наук (январь 1995 г.) изменения являются компенсаторным ответом на другие, из более фундаментальные первичных патологические процессы. Одной возможных и причин нейродегенерации при болезни Альцгеймера родственных заболеваниях является нарушение специфичности обмена липидов, способное в свою очередь вызвать каскад вторичных компенсаторных изменений, в том числе изменение биохимии амилоида бета, белка тау, и баланса реакций оксидативного стресса. В последующих

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