Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Folia Neuropathol. 2012;50(2):101-9.
The road to clarity for postischemic dementia mechanisms has been one fraught with a wide range of complications and numerous revisions with a lack of a final solution. Importantly, brain ischemia is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Data from animal models and clinical pioneering studies of brain ischemia have demonstrated an increase in expression and processing of amyloid precursor protein to a neurotoxin oligomeric β-amyloid peptide. Functional and memory brain restoration after ischemic brain injury is delayed and incomplete due to a lesion related increase in the amount of the neurotoxin amyloid protein. Moreover, ischemic injury is strongly accelerated by aging, too. In this review, we will present our current thinking about biogenesis of amyloid from the amyloid precursor protein in ischemic brain injury, and how this factor presents etiological, therapeutic and diagnostic targets that are now under consideration. Progressive injury of the ischemic brain parenchyma may be caused not only by degeneration of selectively vulnerable neurons destroyed during ischemia but also by acute and chronic damage of resistant areas of the brain and progressive damage in the blood-brain barrier. We propose that in postischemic dementia an initial ischemic injury precedes the cerebrovascular and brain parenchyma accumulation of Alzheimer disease related neurotoxin β-amyloid peptide, which in turn amplifies the neurovascular dysfunction triggering focal ischemic episodes as a vicious cycle preceding final neurodegenerative pathology. Persistent ischemic blood-brain barrier insufficiency with accumulation of neurotoxin β-amyloid protein in the brain tissue, especially in extracellular perivascular space and blood-brain barrier microvessels, may gradually, over a lifetime, progress to brain atrophy and to full-blown ischemic dementia with Alzheimer phenotype.
缺血性痴呆机制的研究之路充满了各种并发症，经过多次修订，仍未找到最终的解决方案。重要的是，脑缺血是全球范围内导致死亡和认知障碍的主要原因。然而，脑缺血后认知能力逐渐下降的机制尚不清楚。动物模型和脑缺血临床开创性研究的数据表明，淀粉样前体蛋白的表达和加工增加，导致神经毒性寡聚β-淀粉样肽。由于与损伤相关的神经毒素淀粉样蛋白数量增加，缺血性脑损伤后的大脑功能和记忆恢复延迟且不完全。此外，衰老也会强烈加速缺血性损伤。在这篇综述中，我们将介绍我们目前对缺血性脑损伤中淀粉样前体蛋白产生淀粉样蛋白的认识，以及这一因素如何呈现出目前正在考虑的病因、治疗和诊断靶点。缺血性脑实质的进行性损伤不仅可能是由于在缺血期间选择性脆弱神经元的退化引起的，还可能是由于大脑的急性和慢性损伤以及血脑屏障的进行性损伤引起的。我们提出，在缺血性痴呆中，初始的缺血性损伤先于与血管性痴呆相关的神经毒素β-淀粉样肽在脑血管和脑实质中的积累，进而放大神经血管功能障碍，引发局灶性缺血发作，形成一个恶性循环，最终导致神经退行性病理。持续性缺血性血脑屏障功能不全，导致神经毒素β-淀粉样蛋白在脑组织中，特别是在血管周围间隙和血脑屏障微血管中蓄积，可能会逐渐导致脑萎缩，并发展为具有阿尔茨海默病表型的完全性缺血性痴呆。
