TRAFFICINAD · The role of neuronal intracellular traffic in Alzheimer´s disease
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2013-04-01 → 2017-03-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Вътрешното транспортиране на протеини в невроните, като например движението на APP и BACE1, определя натрупването на вредни вещества при болестта Алцхаймер. Разбирането на тези процеси помага да се разбере механизмът на невродегенерацията при стареене на мозъка.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
The role of neuronal intracellular traffic in Alzheimer´s disease
Abeta generated by processing of the amyloid precursor protein (APP) by beta- and gamma-secretase is either secreted or retained in endosomes near synapses. APP temporal and subcellular localization is different from its secretases. Therefore intracellular trafficking of APP determines the availability of APP to beta- and gamma-secretase. It remains unknown how the complex geometry, polarity, and aging of neurons can influence APP trafficking. Understanding how intracellular trafficking contributes to AD and how it changes with aging is necessary to develop new mechanistic insights into neurodegeneration in AD. Our main question was: does neuronal intracellular trafficking contribute to Abeta accumulation that leads to AD? By studying the impact of two late-onset risk factors, Bin1 and CD2AP, on the endocytic itinerary of the amyloid precursor protein and of beta-secretase, we found Abeta generation polarized in neurons. Bin1 loss of function increased Abeta generation in axons while CD2AP loss of function increased Abeta in dendrites. Bin1 was polarized to axonal endosomes while CD2AP was polarized to dendritic endosomes. Different mechanisms were utilized by Bin1 and CD2AP to control Abeta generation. Bin1 controlled BACE1 recycling but not APP trafficking, and CD2AP controlled APP sorting for degradation but not BACE1 trafficking. Bin1 was found necessary for the scission of BACE1 tubules off endosomes while CD2AP was necessary for the translocation of APP to the lumen of maturing endosomes. Moreover, we found that Bin1 neuronal isoform could rescue Bin1 loss of function but not ubiquitous Bin1. Our findings established Bin1 and CD2AP as regulators of intracellular trafficking pathways relevant for the amyloidogenic processing of APP causal to AD. Our research has highlighted the importance of understanding the cellular mechanisms of neuronal intracellular trafficking to our knowledge of the etiology of late-onset Alzheimer's disease.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
In neurons of Alzheimer’s disease (AD) there is an aberrant accumulation of beta-amyloid (Aβ) at synapses that renders difficult the formation of new memories for AD patients. Intracellular trafficking abnormalities have been implicated in Aβ accumulation. This research project aims to define how neuronal intracellular trafficking is mechanistically involved in Aβ accumulation that leads to AD. We will determine how the intracellular itinerary of the amyloid precursor protein in neurons influences the generation of Aβ. We will determine the intracellular trafficking of lysosomal hydrolases in neurons and their contribution to the lysosomal clearance of Aβ. Furthermore, we will investigate the mechanism whereby regulators of intracellular trafficking identified as risk-factors for AD contribute to Aβ accumulation. Finally, because aging is the most important risk factor for AD, we will determine if alterations in intracellular trafficking occur in aging, identifying a new mechanism of vulnerability to neurodegeneration in AD. Thus, we will demonstrate how intracellular trafficking is implicated in AD and unravel an important disease mechanism.
Оригинален текст от CORDIS (на английски).
Участници
- FACULDADE DE CIENCIAS MEDICAS DA UNIVERSIDADE NOVA DE LISBOA · LISBOAКоординаторПортугалия
Връзки
Данни: CORDIS, © Европейски съюз