Novel cognitive enhancing strategies for Alzheimer's disease

阿尔茨海默病（AD）是痴呆的主要年龄相关形式，其特征在于认知功能障碍。提高认知能力的策略可能会影响我们老龄人口中很大一部分人的生活质量。在AD中，跨膜淀粉样蛋白前体蛋白（APP）被蛋白水解切割，产生神经毒性淀粉样蛋白-β。然而，在正常情况下，APP被切割以产生可溶性APP（sAPP），其具有神经保护和认知增强作用，其通过sAPP与神经元表面上的未知受体结合来介导。本提案的目的是通过以下方式在探索sAPP的认知增强潜力方面采取必要的后续步骤：1）鉴定神经元细胞表面上sAPP的受体和结合伴侣;以及2）验证所鉴定的受体在sAPP对突触可塑性和抗氧化应激的作用中的作用。将采用一系列生物化学，生物物理和细胞生物学方法，包括对人类诱导多能干细胞（iPSC）衍生神经元的重点研究。sAPP受体及其结合伴侣的鉴定将为模拟AD中sAPP活性的新型药理学方法开辟道路。

Alzheimer's disease (AD), the major age-related form of dementia, is characterised by cognitive dysfunction. Strategies to enhance cognition could impact on quality of life for a significant proportion of our ageing population. In AD the transmembrane amyloid precursor protein (APP) is proteolytically cleaved to generate the neurotoxic amyloid-beta. However, under normal circumstances APP is cleaved to generate soluble APP (sAPP) that has neuroprotective and cognitive-enhancing effects which are mediated by sAPP binding to an unknown receptor on the surface of neurons. The objectives of this proposal are to take the essential next steps in exploring the cognitive enhancing potential of sAPP by: 1) identifying the receptor and binding partners for sAPP on the surface of neuronal cells; and 2) validating the identified receptor in sAPP's actions on synaptic plasticity and protection against oxidative stress. A range of biochemical, biophysical and cell biological approaches will be employed, including focused studies on human induced-pluripotent stem cell (iPSC)-derived neurons. Identification of the sAPP receptor and its binding partners will open the way to novel pharmacological approaches to mimic sAPP activity in AD.